Cyclic peroxides as prodrugs for selective delivery of agents

ABSTRACT

Disclosed herein, inter alia, are prodrug compositions and methods of using the same for treatment and detection of disease. Specifically, disclosed herein is a compound of formula (I) having spiro-fused 1,2,4-trioxolane and piperidine rings, namely, 1,2,4-trioxa-8-azaspiro[4.5]decane. Also disclosed is a pharmaceutical composition containing the compound and a pharmaceutically acceptable carrier.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of the U.S. patent application Ser.No. 15/118,268, filed Aug. 11, 2016, which is the national stage filingunder USC 371 of international application PCT/US2015/015,948, filedFeb. 13, 2015, which claims the benefit of U.S. Provisional PatentApplication No. 61/940,295, filed Feb. 14, 2014, which are incorporatedherein by reference in their entirety and for all purposes.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

This invention was made with government support under grant no.AI094433, awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

BACKGROUND OF THE INVENTION

The majority of chemotherapeutic agents used to treat cancer exhibitserious toxicity, resulting in undesired side effects for patients andreducing efficacy by limiting the doses that can be safely administered.Similarly, many of the therapeutics used to treat infectious diseases,including parasitic diseases, confer undesirable side effects. It wouldbe preferable if such agents could be administered in a prodrug formthat masked the inherent toxicity of the agent from irrelevant,non-diseased tissues, and yet released the fully active drug species atthe desired site of action. Such a technology would have the potentialto increase the therapeutic window of a variety of drugs, possiblyallowing them to be used safely at a more efficacious dose, and withreduced incidence of undesired side-effects for the patient.

In normal cells and tissues, iron remains sequestered in forms that arenon-toxic to the cell, bound to the iron carrying protein transferrinfor example, or bound as heme within hemoglobin. Diseased tissues andcells, on the other hand, can contain higher than normal concentrationsof iron. Many neoplastic cells for example over-express the transferrinreceptor to increase their uptake of iron. Increased iron uptake hasbeen proposed to explain the increased toxicity that iron-dependentendoperoxides like artemisinin exhibit towards cancer cell lines ascompared to normal cells (Efferth, T. Drug Resistance Updates, 2005,8:85-97). In one study, the expression level of the transferrin receptorwas shown to correlate with the cytotoxicity of an artemisininderivative towards HeLa cells (see for example Disbrow, G. L., et alCancer Research, 2005, 65, 10854-10861). Artemisinin and its derivativesare believed to exert their cytotoxic effect via reaction with Fe^(II)and the resulting generation of reactive oxygen and carbon centeredradical species. The cytotoxicity of artemisinin derivatives towardsleukemia, astrocytoma, and breast cancer cell lines can be potentiatedby the addition of exogenous Fe^(II) salts or transferrin (Efferth, T.et al Free Radical Biology & Medicine, 2004, 37, 998-1009; Singh, N. P.et al Life Sciences, 2001, 70, 49-56). U.S. Pat. No. 5,578,637 describesthe use of an endoperoxide moiety (i.e., an artemisinin) to kill cancercells under conditions that enhance intracellular iron concentrations.None of these prior works teach or suggest how higher than normalconcentrations of iron in such cells could be exploited for selectivedelivery of a drug species via an iron-sensitive prodrug moiety.

The blood-scavenging parasites responsible for diseases such as malariaand schistosomiasis also possess biological compartments rich in ferrousiron. In malaria parasites, unbound heme is generated in the parasitedigestive vacuole where hemoglobin is degraded by a number of proteases(See Rosenthal, P. J. in Protease and hemoglobin degradation. MolecularApproaches to Malaria, 2005: p. 311-326). Hence, while the concentrationof unbound, ferrous iron is vanishingly small in human plasma (˜10⁻¹⁶M),significant quantities of ferrous iron are present within malariaparasites (see Robert, A. et al Coordination Chemistry Reviews, 2005,249, p. 1927-1936). The antimalarial drug artemisinin and its relatedsynthetic derivatives are thought to confer their antiparasitic effectvia reaction with ferrous iron and the resulting generation of reactiveoxygen and carbon centered radical species. An excess of iron, andferrous iron in particular, is therefore a distinguishing characteristicof many neoplastic cells and pathogenic parasites.

Among synthetic endoperoxide ring systems, the iron reactivity of1,2,4-trioxolanes has been extensively studied in vitro using modelsystems (see Creek, D. J. et al, J. Pharm. Sci. 2007, 96, 2945-2956).

The use of prodrugs to confer improved properties such as increasedbioavailability or aqueous solubility is a well established concept inthe art of pharmaceutical research. These standard approaches rely onthe action of serum esterases or phosphatases to remove the blocking promoiety and thereby liberate the drug species. The attachment of acytotoxic agent to a targeting moiety such as a protein or antibody viaan acid-labile linker moiety is another known prodrug approach, intendedto deliver a drug moiety to a specific cell or tissue. See U.S. Pat. No.5,306,809. Acid labile linker moieties have also been used to attachdrug species to biopolymers or antibodies where the intention is thatthe lower pH of the diseased tissue serves to trigger release of thedrug moiety. See U.S. Pat. Nos. 4,631,190; 4,997,913; 5,140,013.Antibody-drug conjugates (ADC) are currently being developed for themore selective delivery of therapeutic agents, especially in cancer.Typically a potent drug is conjugated to an antibody that recognizesantigen on a particular cell type of interest. The ADC is internalizedvia receptor mediated endocytosis and the free drug is released, oftenvia an acid labile linker or a reductively labile (disulfide) linker.ADCs are complex and not always as selective as desired because thetargeted antigen can be expressed in normal cells. Insufficiently stablelinkers can also result in spurious drug release from ADCs. Disclosedherein, inter alia, are solutions to these and other problems in theart.

BRIEF SUMMARY OF THE INVENTION

In an aspect is provided a compound, or a pharmaceutically acceptablesalt thereof, having the formula:

wherein L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, L⁹, L¹¹, and L¹² are independently abond, —N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)O-L¹³-L¹⁴-, —O-L¹³-L¹⁴-, —S-L¹³-L¹⁴-,—OC(O)-L¹³-L¹⁴-, —OC(O)N(R¹⁷)-L¹³-L¹⁴-, —OC(O)O-L¹³-L¹⁴-,—OSO₂-L¹³-L¹⁴-, —C(O)N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)-L¹³-L¹⁴-,—S(O)₂N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)S(O)₂-L¹³-L¹⁴-, substituted orunsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene; L¹⁰ is —N(-L¹¹-R¹¹)— or—C((-L¹¹-R¹¹)(-L¹²-R¹²))—; each L¹³ and L¹⁴ are independently selectedfrom a bond, —N(R¹⁷)—, —N(R¹⁷)C(O)O—, —O—, —S—, —OC(O)—, —OC(O)N(R¹⁷)—,—OC(O)O—, —OSO₂—, —C(O)N(R¹⁷)—, —N(R¹⁷)C(O)—, —S(O)₂N(R¹⁷)—,—N(R¹⁷)S(O)₂—, substituted or unsubstituted alkylene, substituted orunsubstituted heteroalkylene, substituted or unsubstitutedcycloalkylene, substituted or unsubstituted heterocycloalkylene,substituted or unsubstituted arylene, or substituted or unsubstitutedheteroarylene; R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹, and R¹², areindependently hydrogen, oxo, halogen, —CX₃, —CN, —SO₂Cl, —SO_(n)R¹⁶,—SO_(v)NR¹³R¹⁴, —NHNH₂, —ONR¹³R¹⁴, —NHC═(O)NHNH₂,—NHC═(O)NR¹³R¹⁴, —N(O)_(m), —NR¹³R¹⁴, —C(O)R¹⁵, —C(O)—OR¹⁵,—C(O)NR¹³R¹⁴, —OR¹⁶, —NR¹³SO₂R¹⁶, —NR¹³C═(O)R¹⁵, —NR¹³C(O)—OR¹⁵,—NR¹³OR¹⁵, —OCX₃, —OCHX₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, aprotein moiety, a detectable moiety, or a drug moiety; R⁵ and R¹¹substituents may be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁶and R¹¹ substituents may be joined to form a substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R² and R³, R⁴ and R⁵, R⁶ and R⁷, R⁸ and R⁹, or R¹¹ and R¹²may be joined to form a substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; eachR¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are independently hydrogen, halogen, —CF₃,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹³and R¹⁴ substituents bonded to the same atom may be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl; R¹⁸ and R¹⁹ are independently hydrogen,halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, a protein moiety, detectable moiety,siderophore moiety, or a drug moiety; R¹⁸ and R¹⁹ may be joined to forma substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, protein moiety, detectable moiety, siderophore moiety,or drug moiety; m and v are independently 1 or 2; n is independently aninteger from 0 to 2; Y is —O—, —S—, —OO—, —CH₂O—, or —OCH₂—; and X isindependently —Cl, —Br, —I, or —F.

In an aspect is provided a pharmaceutical composition including apharmaceutically acceptable excipient and a compound described herein(including in an aspect, embodiment, table, example, or claim), orpharmaceutically acceptable salt thereof.

In an aspect is provided a method of treating a disease in a patient inneed of such treatment, said method including administering atherapeutically effective amount of a compound described herein(including in an aspect, embodiment, table, example, or claim), or apharmaceutically acceptable salt thereof, to the patient.

In an aspect is provided a method of identifying a patient having adisease associated with a cell or organism having an increased Fe^(II)level compared to a standard control, the method including administeringan effective amount of a compound described herein (including in anaspect, embodiment, table, example, or claim), or a pharmaceuticallyacceptable salt thereof, to the patient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. In vivo efficacy of Example 23 (9.5 mg/kg/day, solid line) ascompared to chloroquine (33 mg/kg/day, dashed line) and arterolanetosylate (13.6 mg/kg/day, dotted line) in P. berghei infected mice. Allcompounds were administered to P. berghei infected mice by oral gavageonce a day for three days at the indicated daily dose.

DETAILED DESCRIPTION OF THE INVENTION

Described herein are novel prodrugs capable of the selective release ofan agent (e.g. drug, detectable agent, protein) to biologicalcompartments containing unbound forms of ferrous iron, pharmaceuticalcompositions thereof, methods for their use, and methods for preparingthese prodrugs. Described herein is the use of the prodrugs in thetreatment of parasitic and neoplastic disease, or any condition wherethe targeting of cells or biological compartments with higher thannormal concentrations of a reductant (e.g. ferrous iron) is of benefit(e.g. diagnostic or therapeutic). Examples of the prodrug moietiesdescribed herein include a heterocyclic ring system containing aperoxide bond (e.g. a 1,2,4-trioxane or 1,2,4-trioxolane ring system).The agent (e.g. drug, detectable agent, protein) may be directlyembedded in the structure of the prodrug, or it may be attached via aself-immolating linker. Upon exposure to ferrous iron, or otherbiologically relevant reductants, the peroxide containing heterocyclicundergoes a fragmentation reaction, releasing the agent (e.g. drug,detectable agent, protein), or alternatively unveiling a carbonylfunction in the linker, which then undergoes a spontaneous eliminationreaction to release the tethered agent (e.g. drug, detectable agent,protein). The agent (e.g. drug, detectable agent, protein) can beconjugated to the prodrug via a variety of chemical functionality,including but not limited to a carbonyl, ester, ether, carbamate,carbonate, amine, or thioether.

A. Definitions

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight (i.e., unbranched) or branchednon-cyclic carbon chain (or carbon), or combination thereof, which maybe fully saturated, mono- or polyunsaturated and can include di- andmultivalent radicals, having the number of carbon atoms designated(i.e., C₁-C₁₀ means one to ten carbons). Examples of saturatedhydrocarbon radicals include, but are not limited to, groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, (cyclohexyl)methyl, homologs and isomers of, for example,n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkylgroup is one having one or more double bonds or triple bonds. Examplesof unsaturated alkyl groups include, but are not limited to, vinyl,2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and thehigher homologs and isomers. An alkoxy is an alkyl attached to theremainder of the molecule via an oxygen linker (—O—).

The term “alkylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkyl, asexemplified, but not limited by, —CH₂CH₂CH₂CH₂—. Typically, an alkyl (oralkylene) group will have from 1 to 24 carbon atoms, with those groupshaving 10 or fewer carbon atoms being preferred in the presentinvention. A “lower alkyl” or “lower alkylene” is a shorter chain alkylor alkylene group, generally having eight or fewer carbon atoms. Theterm “alkenylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkene.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched non-cyclicchain, or combinations thereof, including at least one carbon atom andat least one heteroatom selected from the group consisting of O, N, P,Si, and S, and wherein the nitrogen and sulfur atoms may optionally beoxidized, and the nitrogen heteroatom may optionally be quaternized. Theheteroatom(s) O, N, P, S, and Si may be placed at any interior positionof the heteroalkyl group or at the position at which the alkyl group isattached to the remainder of the molecule. Examples include, but are notlimited to: —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃,—Si(CH₃)₃, —CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, —O—CH₃, —O—CH₂—CH₃, and—CN. Up to two or three heteroatoms may be consecutive, such as, forexample, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃.

Similarly, the term “heteroalkylene,” by itself or as part of anothersubstituent, means, unless otherwise stated, a divalent radical derivedfrom heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—. As describedabove, heteroalkyl groups, as used herein, include those groups that areattached to the remainder of the molecule through a heteroatom, such as—C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and/or —SO₂R′. Where“heteroalkyl” is recited, followed by recitations of specificheteroalkyl groups, such as —NR′R″ or the like, it will be understoodthat the terms heteroalkyl and —NR′R″ are not redundant or mutuallyexclusive. Rather, the specific heteroalkyl groups are recited to addclarity. Thus, the term “heteroalkyl” should not be interpreted hereinas excluding specific heteroalkyl groups, such as —NR′R″ or the like.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, mean, unless otherwise stated,non-aromatic cyclic versions of “alkyl” and “heteroalkyl,” respectively,wherein the carbons making up the ring or rings do not necessarily needto be bonded to a hydrogen due to all carbon valencies participating inbonds with non-hydrogen atoms. Additionally, for heterocycloalkyl, aheteroatom can occupy the position at which the heterocycle is attachedto the remainder of the molecule. Examples of cycloalkyl include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl,3-hydroxy-cyclobut-3-enyl-1,2, dione, 1H-1,2,4-triazolyl-5(4H)-one,4H-1,2,4-triazolyl, and the like. Examples of heterocycloalkyl include,but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl,tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A“cycloalkylene” and a “heterocycloalkylene,” alone or as part of anothersubstituent, means a divalent radical derived from a cycloalkyl andheterocycloalkyl, respectively.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “acyl” means, unless otherwise stated, —C(O)R where R is asubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent, which can be a single ring ormultiple rings (preferably from 1 to 3 rings) that are fused together(i.e., a fused ring aryl) or linked covalently. A fused ring aryl refersto multiple rings fused together wherein at least one of the fused ringsis an aryl ring. The term “heteroaryl” refers to aryl groups (or rings)that contain at least one heteroatom such as N, O, or S, wherein thenitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. Thus, the term “heteroaryl” includesfused ring heteroaryl groups (i.e., multiple rings fused togetherwherein at least one of the fused rings is a heteroaromatic ring). A5,6-fused ring heteroarylene refers to two rings fused together, whereinone ring has 5 members and the other ring has 6 members, and wherein atleast one ring is a heteroaryl ring. Likewise, a 6,6-fused ringheteroarylene refers to two rings fused together, wherein one ring has 6members and the other ring has 6 members, and wherein at least one ringis a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to tworings fused together, wherein one ring has 6 members and the other ringhas 5 members, and wherein at least one ring is a heteroaryl ring. Aheteroaryl group can be attached to the remainder of the moleculethrough a carbon or heteroatom. Non-limiting examples of aryl andheteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl,4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl,5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl,5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and6-quinolyl. Substituents for each of the above noted aryl and heteroarylring systems are selected from the group of acceptable substituentsdescribed below. An “arylene” and a “heteroarylene,” alone or as part ofanother substituent, mean a divalent radical derived from an aryl andheteroaryl, respectively. Non-limiting examples of aryl and heteroarylgroups include pyridinyl, pyrimidinyl, thiophenyl, thienyl, furanyl,indolyl, benzoxadiazolyl, benzodioxolyl, benzodioxanyl, thianaphthanyl,pyrrolopyridinyl, indazolyl, quinolinyl, quinoxalinyl, pyridopyrazinyl,quinazolinonyl, benzoisoxazolyl, imidazopyridinyl, benzofuranyl,benzothienyl, benzothiophenyl, phenyl, naphthyl, biphenyl, pyrrolyl,pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl,furylthienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl,benzimidazolyl, isoquinolyl, thiadiazolyl, oxadiazolyl, pyrrolyl,diazolyl, triazolyl, tetrazolyl, benzothiadiazolyl, isothiazolyl,pyrazolopyrimidinyl, pyrrolopyrimidinyl, benzotriazolyl, benzoxazolyl,or quinolyl. The examples above may be substituted or unsubstituted anddivalent radicals of each heteroaryl example above are non-limitingexamples of heteroarylene.

A fused ring heterocyloalkyl-aryl is an aryl fused to aheterocycloalkyl. A fused ring heterocycloalkyl-heteroaryl is aheteroaryl fused to a heterocycloalkyl. A fused ringheterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl.A fused ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkylfused to another heterocycloalkyl. Fused ring heterocycloalkyl-aryl,fused ring heterocycloalkyl-heteroaryl, fused ringheterocycloalkyl-cycloalkyl, or fused ringheterocycloalkyl-heterocycloalkyl may each independently beunsubstituted or substituted with one or more of the substitutentsdescribed herein.

The term “oxo,” as used herein, means an oxygen that is double bonded toa carbon atom.

The term “alkylsulfonyl,” as used herein, means a moiety having theformula —S(O₂)—R′, where R′ is a substituted or unsubstituted alkylgroup as defined above. R′ may have a specified number of carbons (e.g.,“C₁-C₄ alkylsulfonyl”).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,”, “cycloalkyl”,“heterocycloalkyl”, “aryl,” and “heteroaryl”) includes both substitutedand unsubstituted forms of the indicated radical. Preferred substituentsfor each type of radical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″,—NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R′″,—ONR′R″, —NR′C═(O)NR″NR′″R″″, —CN, —NO₂, in a number ranging from zeroto (2m′+1), where m′ is the total number of carbon atoms in suchradical. R, R′, R″, R′″, and R″″ each preferably independently refer tohydrogen, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl (e.g., aryl substituted with 1-3halogens), substituted or unsubstituted heteroaryl, substituted orunsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups.When a compound of the invention includes more than one R group, forexample, each of the R groups is independently selected as are each R′,R″, R′″, and R″″ group when more than one of these groups is present.When R′ and R″ are attached to the same nitrogen atom, they can becombined with the nitrogen atom to form a 4-, 5-, 6-, or 7-memberedring. For example, —NR′R″ includes, but is not limited to,1-pyrrolidinyl and 4-morpholinyl. From the above discussion ofsubstituents, one of skill in the art will understand that the term“alkyl” is meant to include groups including carbon atoms bound togroups other than hydrogen groups, such as haloalkyl (e.g., —CF₃ and—CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and thelike).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for example: —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′,—S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R′″, —ONR′R″,—NR′C═(O)NR″NR′″R″″, —CN, —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy,and fluoro(C₁-C₄)alkyl, in a number ranging from zero to the totalnumber of open valences on the aromatic ring system; and where R′, R″,R′″, and R″″ are preferably independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl. When a compound of theinvention includes more than one R group, for example, each of the Rgroups is independently selected as are each R′, R″, R′″, and R″″ groupswhen more than one of these groups is present.

Two or more substituents may optionally be joined to form aryl,heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-calledring-forming substituents are typically, though not necessarily, foundattached to a cyclic base structure. In one embodiment, the ring-formingsubstituents are attached to adjacent members of the base structure. Forexample, two ring-forming substituents attached to adjacent members of acyclic base structure create a fused ring structure. In anotherembodiment, the ring-forming substituents are attached to a singlemember of the base structure. For example, two ring-forming substituentsattached to a single member of a cyclic base structure create aspirocyclic structure. In yet another embodiment, the ring-formingsubstituents are attached to non-adjacent members of the base structure.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally form a ring of the formula -T-C(O)—(CRR′)_(q)—U—, whereinT and U are independently —NR—, —O—, —CRR′—, or a single bond, and q isan integer of from 0 to 3. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula -A-(CH₂)_(r)—B—, wherein A and B areindependently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′—, or asingle bond, and r is an integer of from 1 to 4. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —(CRR′)_(s)—X′— (C″R″R′″)_(d)—, where s and d are independentlyintegers of from 0 to 3, and X′ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituents R, R′, R″, and R′″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

As used herein, the terms “heteroatom” or “ring heteroatom” are meant toinclude, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), andsilicon (Si).

A “substituent group,” as used herein, means a group selected from thefollowing moieties:

-   -   (A) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,        —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,        —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,        —NHOH, —OCF₃, —OCHF₂, unsubstituted alkyl, unsubstituted        heteroalkyl, unsubstituted cycloalkyl, unsubstituted        heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl,        and    -   (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, substituted with at least one substituent selected        from:        -   (i) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,            —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,            —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,            —NHOH, —OCF₃, —OCHF₂, unsubstituted alkyl, unsubstituted            heteroalkyl, unsubstituted cycloalkyl, unsubstituted            heterocycloalkyl, unsubstituted aryl, unsubstituted            heteroaryl, and        -   (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,            heteroaryl, substituted with at least one substituent            selected from:            -   (a) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,                —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,                —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H,                —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, unsubstituted alkyl,                unsubstituted heteroalkyl, unsubstituted cycloalkyl,                unsubstituted heterocycloalkyl, unsubstituted aryl,                unsubstituted heteroaryl, and            -   (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,                aryl, heteroaryl, substituted with at least one                substituent selected from: oxo,            -   halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,                —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,                —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H,                —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, unsubstituted alkyl,                unsubstituted heteroalkyl, unsubstituted cycloalkyl,                unsubstituted heterocycloalkyl, unsubstituted aryl,                unsubstituted heteroaryl.

A “size-limited substituent” or “size-limited substituent group,” asused herein, means a group selected from all of the substituentsdescribed above for a “substituent group,” wherein each substituted orunsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl.

A “lower substituent” or “lower substituent group,” as used herein,means a group selected from all of the substituents described above fora “substituent group,” wherein each substituted or unsubstituted alkylis a substituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl.

In some embodiments, each substituted group described in the compoundsherein is substituted with at least one substituent group. Morespecifically, in some embodiments, each substituted alkyl, substitutedheteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl,substituted aryl, substituted heteroaryl, substituted alkylene,substituted heteroalkylene, substituted cycloalkylene, substitutedheterocycloalkylene, substituted arylene, and/or substitutedheteroarylene described in the compounds herein are substituted with atleast one substituent group. In other embodiments, at least one or allof these groups are substituted with at least one size-limitedsubstituent group. In other embodiments, at least one or all of thesegroups are substituted with at least one lower substituent group.

In other embodiments of the compounds herein, each substituted orunsubstituted alkyl may be a substituted or unsubstituted C₁-C₂₀ alkyl,each substituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl. In someembodiments of the compounds herein, each substituted or unsubstitutedalkylene is a substituted or unsubstituted C₁-C₂₀ alkylene, eachsubstituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 20 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₈cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 8 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 10 membered heteroarylene.

In some embodiments, each substituted or unsubstituted alkyl is asubstituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and/or each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl. In some embodiments, each substituted orunsubstituted alkylene is a substituted or unsubstituted C₁-C₈ alkylene,each substituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 8 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₇cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 7 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 9 membered heteroarylene. In someembodiments, the compound is a chemical species set forth in theExamples section, figures, or tables below.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds that are prepared with relatively nontoxic acidsor bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galactunoric acids and thelike (see, e.g., Berge et al., Journal of Pharmaceutical Science 66:1-19(1977)). Certain specific compounds of the present invention containboth basic and acidic functionalities that allow the compounds to beconverted into either base or acid addition salts. Otherpharmaceutically acceptable carriers known to those of skill in the artare suitable for the present invention. Salts tend to be more soluble inaqueous or other protonic solvents than are the corresponding free baseforms. In other cases, the preparation may be a lyophilized powder in 1mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH range of 4.5to 5.5, that is combined with buffer prior to use.

Thus, the compounds of the present invention may exist as salts, such aswith pharmaceutically acceptable acids. The present invention includessuch salts. Examples of such salts include hydrochlorides,hydrobromides, sulfates, methanesulfonates, nitrates, maleates,acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates,(−)-tartrates, or mixtures thereof including racemic mixtures),succinates, benzoates, and salts with amino acids such as glutamic acid.These salts may be prepared by methods known to those skilled in theart.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents.

Provided herein are agents (e.g. compounds, proteins, drugs, detectableagents, therapeutic agents) in a prodrug form. Prodrugs of the compoundsdescribed herein are those compounds that readily undergo chemicalchanges under select physiological conditions (e.g. increased Fe^(II)concentration relative to normal physiological levels, increasedreductant levels relative to normal physiological levels) to provide thefinal agents (e.g. compounds, proteins, drugs, detectable agents,therapeutic agents). Additionally, prodrugs can be converted to agents(e.g. compounds, proteins, drugs, detectable agents, therapeutic agents)by chemical or biochemical methods in an ex vivo environment. Prodrugsdescribed herein include compounds that readily undergo chemical changesunder select physiological conditions (e.g. increased Fe^(II)concentration relative to normal physiological levels, increasedreductant levels relative to normal physiological levels) to provideagents (e.g. compounds, proteins, drugs, detectable agents, therapeuticagents) to a biological system (e.g. in a subject, in an infected cell,in a cancer cell, in the extracellular space near an infected cell, inthe extracellular space near a cancer cell from the moieties (e.g.moiety of a protein, drug, detectable agent) attached to the prodrugmoiety and included in the prodrug (e.g. compound of formula I,including embodiments, compound described herein, examples)).

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of thepresent invention.

As used herein, the term “salt” refers to acid or base salts of thecompounds used in the methods of the present invention. Illustrativeexamples of acceptable salts are mineral acid (hydrochloric acid,hydrobromic acid, phosphoric acid, and the like) salts, organic acid(acetic acid, propionic acid, glutamic acid, citric acid and the like)salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like)salts.

Certain compounds of the present invention possess asymmetric carbonatoms (optical or chiral centers) or double bonds; the enantiomers,racemates, diastereomers, tautomers, geometric isomers, stereoisomericforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers areencompassed within the scope of the present invention. The compounds ofthe present invention do not include those which are known in art to betoo unstable to synthesize and/or isolate. The present invention ismeant to include compounds in racemic and optically pure forms.Optically active (R)- and (S)-, or (D)- and (L)-isomers may be preparedusing chiral synthons or chiral reagents, or resolved using conventionaltechniques. When the compounds described herein contain olefinic bondsor other centers of geometric asymmetry, and unless specified otherwise,it is intended that the compounds include both E and Z geometricisomers.

As used herein, the term “isomers” refers to compounds having the samenumber and kind of atoms, and hence the same molecular weight, butdiffering in respect to the structural arrangement or configuration ofthe atoms.

The term “tautomer,” as used herein, refers to one of two or morestructural isomers which exist in equilibrium and which are readilyconverted from one isomeric form to another.

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I), or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areencompassed within the scope of the present invention.

The symbol “

” denotes the point of attachment of a chemical moiety to the remainderof a molecule or chemical formula.

The terms “a” or “an,” as used in herein means one or more. In addition,the phrase “substituted with a[n],” as used herein, means the specifiedgroup may be substituted with one or more of any or all of the namedsubstituents. For example, where a group, such as an alkyl or heteroarylgroup, is “substituted with an unsubstituted C₁-C₂₀ alkyl, orunsubstituted 2 to 20 membered heteroalkyl,” the group may contain oneor more unsubstituted C₁-C₂₀ alkyls, and/or one or more unsubstituted 2to 20 membered heteroalkyls. Moreover, where a moiety is substitutedwith an R substituent, the group may be referred to as “R-substituted.”Where a moiety is R-substituted, the moiety is substituted with at leastone R substituent and each R substituent is optionally different.

Descriptions of compounds of the present invention are limited byprinciples of chemical bonding known to those skilled in the art.Accordingly, where a group may be substituted by one or more of a numberof substituents, such substitutions are selected so as to comply withprinciples of chemical bonding and to give compounds which are notinherently unstable and/or would be known to one of ordinary skill inthe art as likely to be unstable under ambient conditions, such asaqueous, neutral, and several known physiological conditions. Forexample, a heterocycloalkyl or heteroaryl is attached to the remainderof the molecule via a ring heteroatom in compliance with principles ofchemical bonding known to those skilled in the art thereby avoidinginherently unstable compounds.

The terms “polypeptide,” “peptide” and “protein” are usedinterchangeably herein to refer to a polymer of amino acid residues. Theterms apply to amino acid polymers in which one or more amino acidresidue is an artificial chemical mimetic of a corresponding naturallyoccurring amino acid, as well as to naturally occurring amino acidpolymers and non-naturally occurring amino acid polymers. As usedherein, the terms encompass amino acid chains of any length, includingfull length proteins (i.e., antigens), wherein the amino acid residuesare linked by covalent peptide bonds. A protein moiety is a radical of aprotein.

The term “peptidyl” and “peptidyl moiety” means a monovalent peptide.

The term “amino acid” refers to naturally occurring and synthetic aminoacids, as well as amino acid analogs. Naturally occurring amino acidsare those encoded by the genetic code, as well as those amino acids thatare later modified, e.g., hydroxyproline, γ-carboxyglutamate, andO-phosphoserine. Amino acid analogs refers to compounds that have thesame basic chemical structure as a naturally occurring amino acid, i.e.,an α-carbon that is bound to a hydrogen, a carboxyl group, an aminogroup, and an R group, e.g., homoserine, norleucine, methioninesulfoxide, methionine methyl sulfonium. Such analogs have modified Rgroups (e.g., norleucine) or modified peptide backbones, but retain thesame basic chemical structure as a naturally occurring amino acid. Aminoacid mimetics refers to chemical compounds that have a structure that isdifferent from the general chemical structure of an amino acid, but thatfunctions in a manner similar to a naturally occurring amino acid. Anoligomer comprising amino acid mimetics is a peptidomimetic. Apeptidomimetic moiety is a monovalent peptidomimetic.

Amino acids may be referred to herein by either their commonly knownthree letter symbols or by the one-letter symbols recommended by theIUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise,may be referred to by their commonly accepted single-letter codes.

An amino acid or nucleotide base “position” is denoted by a number thatsequentially identifies each amino acid (or nucleotide base) in thereference sequence based on its position relative to the N-terminus (or5′-end). Due to deletions, insertions, truncations, fusions, and thelike that must be taken into account when determining an optimalalignment, in general the amino acid residue number in a test sequencedetermined by simply counting from the N-terminus will not necessarilybe the same as the number of its corresponding position in the referencesequence. For example, in a case where a variant has a deletion relativeto an aligned reference sequence, there will be no amino acid in thevariant that corresponds to a position in the reference sequence at thesite of deletion. Where there is an insertion in an aligned referencesequence, that insertion will not correspond to a numbered amino acidposition in the reference sequence. In the case of truncations orfusions there can be stretches of amino acids in either the reference oraligned sequence that do not correspond to any amino acid in thecorresponding sequence.

The terms “numbered with reference to” or “corresponding to,” when usedin the context of the numbering of a given amino acid or polynucleotidesequence, refers to the numbering of the residues of a specifiedreference sequence when the given amino acid or polynucleotide sequenceis compared to the reference sequence.

A “conservative substitution” as used with respect to amino acids,refers to the substitution of an amino acid with a chemically similaramino acid. Amino acid substitutions which often preserve the structuraland/or functional properties of the polypeptide in which thesubstitution is made are known in the art and are described, forexample, by H. Neurath and R. L. Hill, 1979, in “The Proteins,” AcademicPress, New York. The most commonly occurring exchanges areisoleucine/valine, tyrosine/phenylalanine, aspartic acid/glutamic acid,lysine/arginine, methionine/leucine, aspartic acid/asparagine, glutamicacid/glutamine, leucine/isoleucine, methionine/isoleucine,threonine/serine, tryptophan/phenylalanine, tyrosine/histidine,tyrosine/tryptophan, glutamine/arginine, histidine/asparagine,histidine/glutamine, lysine/asparagine, lysine/glutamine,lysine/glutamic acid, phenylalanine/leucine, phenylalanine/methionine,serine/alanine, serine/asparagine, valine/leucine, andvaline/methionine. The following eight groups each contain amino acidsthat are conservative substitutions for one another: 1) Alanine (A),Glycine (G); 2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N),Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine(L), Methionine (M), Valine (V); 6) Phenylalanine (F), Tyrosine (Y),Tryptophan (W); 7) Serine (S), Threonine (T); and 8) Cysteine (C),Methionine (M) (see, e.g., Creighton, Proteins (1984)). In someembodiments, there may be at least 1, at least 2, at least 3, at least4, at least 5, at least 6, at least 7, at least 8, at least 9, at least10, at least 15, at least 20, at least 25, at least 30, at least 35, orat least 40 conservative substitutions. In some embodiments, there maybe 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, or 40 conservativesubstitutions.

The term “isolated” refers to a nucleic acid, polynucleotide,polypeptide, protein, or other component that is partially or completelyseparated from components with which it is normally associated (otherproteins, nucleic acids, cells, etc.). In some embodiments, an isolatedpolypeptide or protein is a recombinant polypeptide or protein.

The term “antibody” refers to a polypeptide encoded by an immunoglobulingene or functional fragments thereof that specifically binds andrecognizes an antigen. The recognized immunoglobulin genes include thekappa, lambda, alpha, gamma, delta, epsilon, and mu constant regiongenes, as well as the myriad immunoglobulin variable region genes. Lightchains are classified as either kappa or lambda. Heavy chains areclassified as gamma, mu, alpha, delta, or epsilon, which in turn definethe immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively. Anantibody moiety is a radical of an antibody. Non-limiting examples ofantibodies (or functional fragments thereof or antigen-binding fragmentsthereof, derived from such antibodies) that may be included in thecompounds described herein include 3F8, 8H9, Abagovomab, Abciximab,Abrilumab, Actoxumab, Adalimumab, Adecatumumab, Aducanumab, Afelimomab,Afutuzumab, Alacizumab pegol, ALD518, Alemtuzumab, Alirocumab, Altumomabpentetate, Amatuximab, Anatumomab mafenatox, Anifrolumab, Anrukinzumab(IMA-638), Apolizumab, Arcitumomab, Aselizumab, Atinumab, Atlizumab(tocilizumab), Atorolimumab, Bapineuzumab, Basiliximab, Bavituximab,Bectumomab, Belimumab, Benralizumab, Bertilimumab, Besilesomab,Bevacizumab, Bezlotoxumab, Biciromab, Bimagrumab, Bivatuzumabmertansine, Blinatumomab, Blosozumab, Brentuximab vedotin, Briakinumab,Brodalumab, Canakinumab, Cantuzumab mertansine, Cantuzumab ravtansine,Caplacizumab, Capromab pendetide, Carlumab, Catumaxomab, CC49,cBR96-doxorubicin immunoconjugate, Cedelizumab, Certolizumab pegol,Cetuximab, Ch.14.18, Citatuzumab bogatox, Cixutumumab, Clazakizumab,Clenoliximab, Clivatuzumab tetraxetan, Conatumumab, Concizumab,Crenezumab, CR6261, Dacetuzumab, Daclizumab, Dalotuzumab, Daratumumab,Demcizumab, Denosumab, Detumomab, Dinutuximab, Diridavumab, Dorlimomabaritox, Drozitumab, Duligotumab, Dupilumab, Durvalumab, Dusigitumab,Ecromeximab, Eculizumab, Edobacomab, Edrecolomab, Efalizumab, Efungumab,Eldelumab, Elotuzumab, Elsilimomab, Emibetuzumab, Enavatuzumab,Enfortumab vedotin, Enlimomab pegol, Enokizumab, Enoticumab,Ensituximab, Epitumomab cituxetan, Epratuzumab, Erlizumab, Ertumaxomab,Etaracizumab, Etrolizumab, Evinacumab, Evolocumab, Exbivirumab,Fanolesomab, Faralimomab, Farletuzumab, Fasinumab, FBTA05, Felvizumab,Fezakinumab, Ficlatuzumab, Figitumumab, Flanvotumab, Fletikumab,Fontolizumab, Foralumab, Foravirumab, Fresolimumab, Fulranumab,Futuximab, Galiximab, Ganitumab, Gantenerumab, Gavilimomab, Gemtuzumabozogamicin, Gevokizumab, Girentuximab, Glembatumumab vedotin, Golimumab,Gomiliximab, Guselkumab, Ibalizumab, Ibritumomab tiuxetan, Icrucumab,Igovomab, IMAB362, Imciromab, Imgatuzumab, Inclacumab, Indatuximabravtansine, Infliximab, Intetumumab, Inolimomab, Inotuzumab ozogamicin,Ipilimumab, Iratumumab, Itolizumab, Ixekizumab, Keliximab, Labetuzumab,Lambrolizumab, Lampalizumab, Lebrikizumab, Lemalesomab, Lerdelimumab,Lexatumumab, Libivirumab, Lifastuzumab vedotin, Ligelizumab, Lintuzumab,Lirilumab, Lodelcizumab, Lorvotuzumab mertansine, Lucatumumab, Lulizumabpegol, Lumiliximab, Mapatumumab, Margetuximab, Maslimomab, Mavrilimumab,Matuzumab, Mepolizumab, Metelimumab, Milatuzumab, Minretumomab,Mitumomab, Mogamulizumab, Morolimumab, Motavizumab, Moxetumomabpasudotox, Muromonab-CD3, Nacolomab tafenatox, Namilumab, Naptumomabestafenatox, Narnatumab, Natalizumab, Nebacumab, Necitumumab,Nerelimomab, Nesvacumab, Nimotuzumab, Nivolumab, Nofetumomab merpentan,Obiltoxaximab, Ocaratuzumab, Ocrelizumab, Odulimomab, Ofatumumab,Olaratumab, Olokizumab, Omalizumab, Onartuzumab, Ontuxizumab,Oportuzumab monatox, Oregovomab, Orticumab, Otelixizumab, Otlertuzumab,Oxelumab, Ozanezumab, Ozoralizumab, Pagibaximab, Palivizumab,Panitumumab, Pankomab, Panobacumab, Parsatuzumab, Pascolizumab,Pateclizumab, Patritumab, Pembrolizumab, Pemtumomab, Perakizumab,Pertuzumab, Pexelizumab, Pidilizumab, Pinatuzumab vedotin, Pintumomab,Placulumab, Polatuzumab vedotin, Ponezumab, Priliximab, Pritoxaximab,Pritumumab, PRO 140, Quilizumab, Racotumomab, Radretumab, Rafivirumab,Ramucirumab, Ranibizumab, Raxibacumab, Regavirumab, Reslizumab,Rilotumumab, Rituximab, Robatumumab, Roledumab, Romosozumab,Rontalizumab, Rovelizumab, Ruplizumab, Samalizumab, Sarilumab, Satumomabpendetide, Secukinumab, Seribantumab, Setoxaximab, Sevirumab,Sibrotuzumab, SGN-CD19A, SGN-CD33A, Sifalimumab, Siltuximab, Simtuzumab,Siplizumab, Sirukumab, Sofituzumab vedotin, Solanezumab, Solitomab,Sonepcizumab, Sontuzumab, Stamulumab, Sulesomab, Suvizumab, Tabalumab,Tacatuzumab tetraxetan, Tadocizumab, Talizumab, Tanezumab, Taplitumomabpaptox, Tarextumab, Tefibazumab, Telimomab aritox, Tenatumomab,Teneliximab, Teplizumab, Teprotumumab, TGN1412, Ticilimumab(tremelimumab), Tildrakizumab, Tigatuzumab, TNX-650, Tocilizumab(atlizumab), Toralizumab, Tositumomab, Tovetumab, Tralokinumab,Trastuzumab, TRBS07, Tregalizumab, Tremelimumab, Tucotuzumabcelmoleukin, Tuvirumab, Ublituximab, Urelumab, Urtoxazumab, Ustekinumab,Vantictumab, Vapaliximab, Varlilumab, Vatelizumab, Vedolizumab,Veltuzumab, Vepalimomab, Vesencumab, Visilizumab, Volociximab,Vorsetuzumab mafodotin, Votumumab, Zalutumumab, Zanolimumab, Zatuximab,Ziralimumab, and Zolimomab aritox.

An exemplary immunoglobulin (antibody) structural unit comprises atetramer. Each tetramer is composed of two identical pairs ofpolypeptide chains, each pair having one “light” (about 25 kDa) and one“heavy” chain (about 50-70 kDa). The N-terminus of each chain defines avariable region of about 100 to 110 or more amino acids primarilyresponsible for antigen recognition. The terms “variable heavy chain,”“V_(H),” or “VH” refer to the variable region of an immunoglobulin heavychain, including an Fv, scFv, dsFv or Fab; while the terms “variablelight chain,” “V_(L)” or “VL” refer to the variable region of animmunoglobulin light chain, including of an Fv, scFv, dsFv or Fab.

Examples of antibody functional fragments (e.g., antigen-bindingfragments) include, but are not limited to, complete antibody molecules,antibody fragments, such as Fv, single chain Fv (scFv), complementaritydetermining regions (CDRs), VL (light chain variable region), VH (heavychain variable region), Fab, F(ab)2′ and any combination of those or anyother functional portion of an immunoglobulin peptide capable of bindingto target antigen (see, e.g., FUNDAMENTAL IMMUNOLOGY (Paul ed., 4th ed.2001). As appreciated by one of skill in the art, various antibodyfragments can be obtained by a variety of methods, for example,digestion of an intact antibody with an enzyme, such as pepsin; or denovo synthesis. Antibody fragments are often synthesized de novo eitherchemically or by using recombinant DNA methodology. Thus, the termantibody, as used herein, includes antibody fragments either produced bythe modification of whole antibodies, or those synthesized de novo usingrecombinant DNA methodologies (e.g., single chain Fv) or thoseidentified using phage display libraries (see, e.g., McCafferty et al.,(1990) Nature 348:552). The term “antibody” also includes bivalent orbispecific molecules, diabodies, triabodies, and tetrabodies. Bivalentand bispecific molecules are described in, e.g., Kostelny et al. (1992)J. Immunol. 148:1547, Pack and Pluckthun (1992) Biochemistry 31:1579,Hollinger et al. (1993), PNAS. USA 90:6444, Gruber et al. (1994) JImmunol. 152:5368, Zhu et al. (1997) Protein Sci. 6:781, Hu et al.(1996) Cancer Res. 56:3055, Adams et al. (1993) Cancer Res. 53:4026, andMcCartney, et al. (1995) Protein Eng. 8:301.

A “label” or a “detectable agent” is a composition detectable byspectroscopic, photochemical, biochemical, immunochemical, chemical,magnetic resonance imaging, or other physical means. For example, usefuldetectable agents include ³²P, fluorescent dyes, electron-densereagents, enzymes (e.g., as commonly used in an ELISA), biotin,digoxigenin, paramagnetic molecules, paramagnetic nanoparticles,ultrasmall superparamagnetic iron oxide (“USPIO”) nanoparticles, USPIOnanoparticle aggregates, nanoparticle contrast agents, liposomes orother delivery vehicles containing Gadolinium chelate (“Gd-chelate”)molecules, Gadolinium, radioisotopes, radionuclides (e.g. carbon-11,nitrogen-13, oxygen-15, fluorine-18, rubidium-82), fluorodeoxyglucose(e.g. fluorine-18 labeled), fluorodeoxyglucose nucleotide or nucleoside(e.g. fluorine-18 labeled A, C, G, or T), gamma ray emittingradionuclides, positron-emitting radionuclide, radiolabeled glucose,radiolabeled water, radiolabeled ammonia, biocolloids, microbubbles(e.g. including microbubble shells including albumin, galactose, lipid,and/or polymers; microbubble gas core including air, heavy gas(es),perfluorcarbon, nitrogen, octafluoropropane, perflexane lipidmicrosphere, perflutren, etc.), iodinated contrast agents (e.g. iohexol,iodixanol, ioversol, iopamidol, ioxilan, iopromide, diatrizoate,metrizoate, ioxaglate), barium sulfate, thorium dioxide, gold, goldnanoparticles, gold nanoparticle aggregates, fluorophores, two-photonfluorophores, or haptens and proteins or other entities which can bemade detectable, e.g., by incorporating a radiolabel into a peptide orantibody specifically reactive with a target peptide. Detectable agentsalso include any of the above compositions encapsulated innanoparticles, particles, aggregates, coated with additionalcompositions, derivatized for binding to a targeting agent (e.g.antibody or antigen binding fragment). A detectable moiety is a radicalof a detectable agent.

The terms “fluorophore” or “fluorescent agent” are used interchangeablyand refer to a composition (e.g. compound) that can absorb light at oneor more wavelengths and re-emit light at one or more longer wavelengths,relative to the one or more wavelengths of absorbed light. Examples offluorophores that may be included in the compositions described hereininclude fluorescent proteins, xanthene derivatives (e.g. fluorescein,rhodamine, Oregon green, eosin, or Texas red), cyanine and derivatives(e.g. cyanine, indocarbocyanine, oxacarbocyanine, thiacarbocyanine ormerocyanine), napththalene derivatives (e.g. dansyl or prodanderivatives), coumarin and derivatives, oxadiazole derivatives (e.g.pyridyloxazole, nitrobenzoxadiazole or benzoxadiazole), anthracenederivatives (e.g. anthraquinones, DRAQ5, DRAQ7, or CyTRAK Orange),pyrene derivatives (e.g. cascade blue and derivatives), oxazinederivatives (e.g. Nile red, Nile blue, cresyl violet, oxazine 170),acridine derivatives (e.g. proflavin, acridine orange, acridine yellow),arylmethine derivatives (e.g. auramine, crystal violet, malachitegreen), tetrapyrrole derivatives (e.g. porphin, phthalocyanine,bilirubin), CF Dye™, DRAQ™, CyTRAK™, BODIPY™, Alexa Fluor™, DyLightFluor™, Atto™, Tracy™, FluoProbes™, Abberior Dyes™, DY™ dyes, MegaStokesDyes™, Sulfo Cy™, Seta™ dyes, SeTau™ dyes, Square Dyes™, Quasar™ dyes,Cal Fluor™ dyes, SureLight Dyes™, PerCP™, Phycobilisomes™, APC™, APCXL™,RPE™, and/or BPE™. A fluorescent moiety is a radical of a fluorescentagent.

The term “drug” is used in accordance with its common meaning and refersto a substance which has a physiological effect (e.g. beneficial effect,is useful for treating a subject) when introduced into or to a subject(e.g. in or on the body of a subject or patient). A drug moiety is aradical of a drug.

The term “siderophore” is used in accordance with its common meaning andrefers to a high-affinity iron chelating compound that may be secretedby a microorganism (e.g., bacteria, fungi, grasses). Non-limitingexamples of siderophores include catecholates (e.g., phenolates),hydroxamates, carboxylates (e.g., derivatives of citric acid),ferrichrome, desferrioxamine B (deferoxamine), desferrioxamine E,fusarinine C, ornibactin, rhodotorulic acid, enterobactin,bacillibactin, vibriobactin, azotobactin, pyoverdine, yersiniabactin,aerobactin, simochelin, alcaligin, mycobactin, staphyloferrin A, andpetrobactin. In embodiments, a siderophore may chelate a non-iron metal(e.g., aluminum, gallium, chromium, copper, zinc, lead, manganese,cadmium vanadium indium, plutonium, or uranium). A sideropohore moietyis a radical of a siderophore. Additional non-limiting examples of asiderophore include Achromobactin, Acinetobactin, Acinetoferrin,Aerobactin, Aeruginic, Agrobactin, Agrobactin A, Albomycin 271,Alcaligin 230, Alterobactin A, Alterobactin B, Aminochelin 262,Amonabactin P693, Amonabactin P750, Amonabactin T732, Amonabactin T789,Amphibactin B, Amphibactin C, Amphibactin D, Amphibactin E, AmphibactinF, Amphibactin G, Amphibactin H, Amphibactin I, Amycolachrome 235,Anachelin 1, Anachelin 2, Anguibactin 247, Aquachelin A, Aquachelin B,Aquachelin C, 2, Aquachelin D, Arthrobactin 199, Asperchrome A,Asperchrome B1, Asperchrome B2, Asperchrome B3, Asperchrome C,Asperchrome D1, Asperchrome D2, Asperchrome D3, Asperchrome E,Asperchrome F1, Asperchrome F2, Asperchrome F3, Aspergillic acid, Avenicacid, Azotobactin 236, Azotobactin D, Azotobactin 87, Azotochelin 236,Azoverdin 174, Bacillibactin 85, Basidiochrome 46, Bisucaberin 232,Carboxymycobactin 107, Carboxymycobactin 1, Carboxymycobactin 2,Carboxymycobactin 3, Carboxymycobactin 4, Cepabactin 266, Chrysobactin261, Citrate 260, Coelichelin 72, 3, Coprogen 51, Coprogen B,Corynebactin 84, Deoxydistichonic acid, 2′-Deoxymugineic acid,Deoxyschizokinen 251, Des(diserylglycyl)-ferrirhodin 45,Desacetylcoprogen 52, Desferrioxamine A1, Desferrioxamine A2,Desferrioxamine B, Desferrioxamine D1, Desferrioxamine D2,Desferrioxamine E, Desferrioxamine Et1 21A, Desferrioxamine Et2 21B,Desferrioxamine Et3 21C, Desferrioxamine G1, Desferrioxamine G2A,Desferrioxamine G2B, Desferrioxamine G2C, Desferrioxamine H,Desferrioxamine P1, Desferrioxamine T1, Desferrioxamine T2,Desferrioxamine T3, Desferrioxamine T7, Desferrioxamine T8,Desferrioxamine Te1 21D, Desferrioxamine Te2 21E Desferrioxamine Te321F, Desferrioxamine X1, Desferrioxamine X2, 4, Desferrioxamine X3,Desferrioxamine X4, Desferrithiocin, 2,3-Dihydroxybenzoylserine, Dimerumacid, Dimethylcoprogen, Dimethylneocoprogen I, Dimethyltriornicin,Distichonic acid, Enantio Rhizoferrin, Enantio-Pyochelin, Enterobactin,Enterochelin, Exochelin MN, Exochelin MS, Ferrichrome, Ferrichrome A,Ferrichrome C, Ferrichrysin, Ferricrocin, Ferrimycin A, Ferrirhodin,Ferrirubin, Ferrocin A, Fluvibactin, Formobactin, Fusarinine A,Fusarinine B, Fusarinine C, Heterobactin A, Heterobactin B,Hydroxycopropen, Hydroxyisoneocoprogen I, 3-Hydroxymugineic acid, 5,Hydroxy-neocoprogen I, Isoneocoprogen I, Isopyoverdin BTP1, Isopyoverdin6.7, Isopyoverdin 7.13, Isopyoverdin 90-33, Isopyoverdin 90-44,Isopyoverdin 10.7, Isotriornicin, Itoic acid, Loihichelin A, LoihichelinB, Loihichelin C, Loihichelin D, Loihichelin E, Loihichelin F,Maduraferrin, Malonichrome, Marinobactin A, Marinobactin B, MarinobactinC, Marinobactin D1, Marinobactin D2, Marinobactin E, Micacocidin,Mugineic acid, Mycobactin A, Mycobactin Av, Mycobactin F, Mycobactin H,Mycobactin J, Mycobactin M, Mycobactin N, 6, Mycobactin NA, MycobactinP, Mycobactin R, Mycobactin S, Mycobactin T, Myxochelin, Nannochelin A,Nannochelin B, Nannochelin C, Neocoprogen I, Neocoprogen II,Neurosporin, Nocobactin, Nocobactin NA, Ochrobactin A, Ochrobactin B,Ochrobactin C, Ornibactin-C4, Ornibactin-C6, Ornibactin-C8,Ornicorrugatin, palmitoylcoprogen, Parabactin, Parabactin A,Petrobactin, Petrobactin disulphonate, Petrobactin sulphonate,Pistillarin, Protochelin, Pseudoalterobactin A, Pseudoalterobactin B,Pseudobactin 112, Pseudobactin 589A, 7, Putrebactin, Pyochelin,Pyoverdin A214, Pyoverdin BTP2, Pyoverdin C, Pyoverdin CHAO, PyoverdinD-TR133, Pyoverdin E, Pyoverdin G R Pyoverdin GM, Pyoverdin I-III,Pyoverdin P19, Pyoverdin Pau, Pyoverdin PL8, Pyoverdin PVD, PyoverdinR′, Pyoverdin Thai, Pyoverdin TII, Pyoverdin 1, Pyoverdin 11370,Pyoverdin 13525, Pyoverdin 1547, Pyoverdin 17400, Pyoverdin 18-1,Pyoverdin 19310, Pyoverdin 2192, Pyoverdin 2392, Pyoverdin 2461,Pyoverdin 2798, Pyoverdin 51W, Pyoverdin 9AW, Pyoverdin 90-51, Pyoverdin95-275, Pyoverdin 96-312, Pyoverdin 96-318, Pyoverdin, Pyoverdin 6.1,Pyoverdin 6.2, Pyoverdin 6.3, Pyoverdin 6.4, Pyoverdin 6.5, Pyoverdin6.6, Pyoverdin 6.8, Pyoverdin 7.1, Pyoverdin 7.2, Pyoverdin 7.3,Pyoverdin 7.4, Pyoverdin 7.5, Pyoverdin 7.6, Pyoverdin 7.7, Pyoverdin7.8, Pyoverdin 7.9, Pyoverdin 7.10, Pyoverdin 7.11, Pyoverdin 7.12,Pyoverdin 7.14, Pyoverdin 7.15, Pyoverdin 7.16, Pyoverdin 7.17,Pyoverdin 7.18, Pyoverdin 7.19, Pyoverdin 8.1, Pyoverdin 8.2, Pyoverdin8.3, Pyoverdin 8.4, Pyoverdin 8.5, Pyoverdin 8.6, Pyoverdin 8.7,Pyoverdin 8.8, Pyoverdin 8.9, Pyoverdin 9.1, Pyoverdin 9.2, Pyoverdin9.3, Pyoverdin 9.4, Pyoverdin 9.5, Pyoverdin 9.6, Pyoverdin 9.7,Pyoverdin 9.8, Pyoverdin 9.9, Pyoverdin 9.10, Pyoverdin 9.11, Pyoverdin9.12, Pyoverdin 10.1, Pyoverdin 10.2, Pyoverdin 10.3, Pyoverdin 10.4,Pyoverdin 10.5, Pyoverdin 10.6, Pyoverdin 10.8, Pyoverdin 10.9,Pyoverdin 10.10, Pyoverdin 11.1, Pyoverdin 11.2, Pyoverdin 12, Pyoverdin12.1, Pyoverdin 12.2, Pyridoxatin, Quinolobactin, Rhizobactin, 10,Rhizobactin, Rhizoferrin, Rhizoferrin analogues 88A-88E, Rhodotrulicacid, Salmochelin S1, Salmochelin S2, Salmochelin S4, Salmochelin SX,Salmycin A, Schizokinen, Serratiochelin, Siderochelin A, Snychobactin A,Snychobactin B, Snychobactin C, Staphyloferrin A, Staphyloferrin B,Tetraglycine ferrichrome, Thiazostatin, Triacetylfusarinine, Triornicin,Vibriobactin, Vibrioferrin, Vicibactin, Vulnibactin, and Yersiniabactin.

The terms “treating” or “treatment” refers to any indicia of success inthe treatment or amelioration of an injury, disease, pathology orcondition, including any objective or subjective parameter such asabatement; remission; diminishing of symptoms or making the injury,pathology or condition more tolerable to the patient; slowing in therate of degeneration or decline; making the final point of degenerationless debilitating; improving a patient's physical or mental well-being.The treatment or amelioration of symptoms can be based on objective orsubjective parameters; including the results of a physical examination,neuropsychiatric exams, and/or a psychiatric evaluation. For example,certain methods herein treat cancer. For example certain methods hereintreat cancer by decreasing a symptom of cancer. Symptoms of cancer wouldbe known or may be determined by a person of ordinary skill in the art.The term “treating” and conjugations thereof, include prevention of aninjury, pathology, condition, or disease. For example, certain methodsherein treat infectious diseases (e.g., malaria, bacterial diseases,viral diseases, parasitic diseases). For example certain methods hereintreat infectious diseases (e.g., malaria, bacterial diseases, viraldiseases, parasitic diseases) by decreasing a symptom of the infectiousdisease (e.g., malaria, bacterial diseases, viral diseases, parasiticdiseases). For example certain methods herein treat infectious diseases(e.g., malaria, bacterial diseases, viral diseases, parasitic diseases)by decreasing the level or viability or amount of the infectious agent(e.g., bacterium, virus, parasite).

An “effective amount” is an amount sufficient to accomplish a statedpurpose (e.g. achieve the effect for which it is administered, treat adisease, reduce enzyme activity, increase enzyme activity, reduceprotein function, reduce one or more symptoms of a disease orcondition). An example of an “effective amount” is an amount sufficientto contribute to the treatment, prevention, or reduction of a symptom orsymptoms of a disease, which could also be referred to as a“therapeutically effective amount.” A “reduction” of a symptom orsymptoms (and grammatical equivalents of this phrase) means decreasingof the severity or frequency of the symptom(s), or elimination of thesymptom(s). A “prophylactically effective amount” of a drug or prodrugis an amount of a drug or prodrug that, when administered to a subject,will have the intended prophylactic effect, e.g., preventing or delayingthe onset (or reoccurrence) of an injury, disease, pathology orcondition, or reducing the likelihood of the onset (or reoccurrence) ofan injury, disease, pathology, or condition, or their symptoms. The fullprophylactic effect does not necessarily occur by administration of onedose, and may occur only after administration of a series of doses.Thus, a prophylactically effective amount may be administered in one ormore administrations. The exact amounts will depend on the purpose ofthe treatment, and will be ascertainable by one skilled in the art usingknown techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms(vols. 1-3, 1992); Lloyd, The Art, Science and Technology ofPharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999);and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003,Gennaro, Ed., Lippincott, Williams & Wilkins).

The term “associated” or “associated with” in the context of a substanceor substance activity or function associated with a disease (e.g.cancer) means that the disease (e.g. cancer) is caused by (in whole orin part), or a symptom of the disease is caused by (in whole or in part)the substance or substance activity or function. As used herein, what isdescribed as being associated with a disease, if a causative agent,could be a target for treatment of the disease. For example, a diseaseassociated with an infectious organism may be treated with an agent(e.g. compound as described herein) effective for decreasing the amountof the infectious organism.

“Control” or “control experiment” or “standard control” is used inaccordance with its plain ordinary meaning and refers to an experimentin which the subjects or reagents of the experiment are treated as in aparallel experiment except for omission of a procedure, reagent, orvariable of the experiment. In some instances, the control is used as astandard of comparison in evaluating experimental effects.

“Contacting” is used in accordance with its plain ordinary meaning andrefers to the process of allowing at least two distinct species (e.g.chemical compounds including biomolecules, or cells) to becomesufficiently proximal to react, interact or physically touch. It shouldbe appreciated, however, that the resulting reaction product can beproduced directly from a reaction between the added reagents or from anintermediate from one or more of the added reagents which can beproduced in the reaction mixture. The term “contacting” may includeallowing two species to react, interact, or physically touch, whereinthe two species may be a compound as described herein and a protein orenzyme. In some embodiments contacting includes allowing a compounddescribed herein to interact with a protein or enzyme.

As defined herein, the term “inhibition”, “inhibit”, “inhibiting” andthe like in reference to a protein-inhibitor (e.g. antagonist)interaction means negatively affecting (e.g. decreasing) the level ofactivity or function of the protein relative to the level of activity orfunction of the protein in the absence of the inhibitor. In someembodiments inhibition refers to reduction of a disease or symptoms ofdisease. Thus, inhibition may include, at least in part, partially ortotally blocking stimulation, decreasing, preventing, or delayingactivation, or inactivating, desensitizing, or down-regulating signaltransduction or enzymatic activity or the amount of a protein.

As defined herein, the term “activation”, “activate”, “activating” andthe like in reference to a protein-activator (e.g. agonist) interactionmeans positively affecting (e.g. increasing) the activity or function ofthe protein relative to the activity or function of the protein in theabsence of the activator (e.g. compound described herein). Thus,activation may include, at least in part, partially or totallyincreasing stimulation, increasing or enabling activation, oractivating, sensitizing, or up-regulating signal transduction orenzymatic activity or the amount of a protein decreased in a disease.Activation may include, at least in part, partially or totallyincreasing stimulation, increasing or enabling activation, oractivating, sensitizing, or up-regulating signal transduction orenzymatic activity or the amount of a protein.

The term “modulator” refers to a composition that increases or decreasesthe level of a target molecule or the function of a target molecule. Inembodiments, a modulator is an anti-cancer agent. In embodiments, amodulator is an anti-infective agent. In embodiments, a modulator is ananti-malarial agent.

“Anti-cancer agent” or “anti-cancer drug” is used in accordance with itsplain ordinary meaning and refers to a composition (e.g. compound, drug,antagonist, inhibitor, modulator) having antineoplastic properties orthe ability to inhibit the growth or proliferation of cells. In someembodiments, an anti-cancer agent is a chemotherapeutic. In someembodiments, an anti-cancer agent is an agent approved by the FDA orsimilar regulatory agency of a country other than the USA, for treatingcancer. In embodiments, an anti-cancer agent is an agent withantineoplastic properties that has not (e.g., yet) been approved by theFDA or similar regulatory agency of a country other than the USA, fortreating cancer. Examples of anti-cancer agents include, but are notlimited to, MEK (e.g. MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g.XL518, CI-1040, PD035901, selumetinib/AZD6244, GSK1120212/trametinib,GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059,TAK-733, PD318088, AS703026, BAY 869766), alkylating agents (e.g.,cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan,mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards(e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan),ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa),alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine,lomusitne, semustine, streptozocin), triazenes (decarbazine)),anti-metabolites (e.g., 5-azathioprine, leucovorin, capecitabine,fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analog(e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil,floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine,thioguanine, pentostatin), etc.), plant alkaloids (e.g., vincristine,vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel,docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan,amsacrine, etoposide (VP16), etoposide phosphate, teniposide, etc.),antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin,epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin,etc.), platinum-based compounds (e.g. cisplatin, oxaloplatin,carboplatin), anthracenedione (e.g., mitoxantrone), substituted urea(e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine),adrenocortical suppressant (e.g., mitotane, aminoglutethimide),epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin,doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), inhibitors ofmitogen-activated protein kinase signaling (e.g. U0126, PD98059,PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006,wortmannin, or LY294002), mTOR inhibitors, antibodies (e.g., rituxan),5-aza-2′-deoxycytidine, doxorubicin, vincristine, etoposide,gemcitabine, imatinib (Gleevec®), geldanamycin,17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), bortezomib,trastuzumab, anastrozole; angiogenesis inhibitors; antiandrogen,antiestrogen; antisense oligonucleotides; apoptosis gene modulators;apoptosis regulators; arginine deaminase; BCR/ABL antagonists; betalactam derivatives; bFGF inhibitor; bicalutamide; camptothecinderivatives; casein kinase inhibitors (ICOS); clomifene analogues;cytarabine dacliximab; dexamethasone; estrogen agonists; estrogenantagonists; etanidazole; etoposide phosphate; exemestane; fadrozole;finasteride; fludarabine; fluorodaunorunicin hydrochloride; gadoliniumtexaphyrin; gallium nitrate; gelatinase inhibitors; gemcitabine;glutathione inhibitors; hepsulfam; immunostimulant peptides;insulin-like growth factor-1 receptor inhibitor; interferon agonists;interferons; interleukins; letrozole; leukemia inhibiting factor;leukocyte alpha interferon; leuprolide+estrogen+progesterone;leuprorelin; matrilysin inhibitors; matrix metalloproteinase inhibitors;MIF inhibitor; mifepristone; mismatched double stranded RNA; monoclonalantibody; mycobacterial cell wall extract; nitric oxide modulators;oxaliplatin; panomifene; pentrozole; phosphatase inhibitors; plasminogenactivator inhibitor; platinum complex; platinum compounds; prednisone;proteasome inhibitors; protein A-based immune modulator; protein kinaseC inhibitor; protein tyrosine phosphatase inhibitors; purine nucleosidephosphorylase inhibitors; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; ribozymes; signal transductioninhibitors; signal transduction modulators; single chain antigen-bindingprotein; stem cell inhibitor; stem-cell division inhibitors; stromelysininhibitors; synthetic glycosaminoglycans; tamoxifen methiodide;telomerase inhibitors; thyroid stimulating hormone; translationinhibitors; tyrosine kinase inhibitors; urokinase receptor antagonists;steroids (e.g., dexamethasone), finasteride, aromatase inhibitors,gonadotropin-releasing hormone agonists (GnRH) such as goserelin orleuprolide, adrenocorticosteroids (e.g., prednisone), progestins (e.g.,hydroxyprogesterone caproate, megestrol acetate, medroxyprogesteroneacetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol),antiestrogen (e.g., tamoxifen), androgens (e.g., testosteronepropionate, fluoxymesterone), antiandrogen (e.g., flutamide),immunostimulants (e.g., Bacillus Calmette-Guérin (BCG), levamisole,interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g.,anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonalantibodies), immunotoxins (e.g., anti-CD33 monoclonalantibody-calicheamicin conjugate, anti-CD22 monoclonalantibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy(e.g., anti-CD20 monoclonal antibody conjugated to ¹¹¹In, ⁹⁰Y, or ¹³¹I,etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin,epirubicin, topotecan, itraconazole, vindesine, cerivastatin,vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan,clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib,gefitinib, EGFR inhibitors, epidermal growth factor receptor(EGFR)-targeted therapy or therapeutic (e.g. gefitinib (Iressa™),erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™),panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib/BIBW2992,CI-1033/canertinib, neratinib/HKI-272, CP-724714, TAK-285, AST-1306,ARRY334543, ARRY-380, AG-1478, dacomitinib/PF299804, OSI-420/desmethylerlotinib, AZD8931, AEE788, pelitinib/EKB-569, CUDC-101, WZ8040, WZ4002,WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib,sunitinib, dasatinib, pyrrolo benzodiazepines (e.g. tomaymycin),carboplatin, CC-1065 and CC-1065 analogs including amino-CBIs, nitrogenmustards (such as chlorambucil and melphalan), dolastatin and dolastatinanalogs (including auristatins: eg. monomethyl auristatin E),anthracycline antibiotics (such as doxorubicin, daunorubicin, etc.),duocarmycins and duocarmycin analogs, enediynes (such asneocarzinostatin and calicheamicins), leptomycin derivaties,maytansinoids and maytansinoid analogs (e.g. mertansine), methotrexate,mitomycin C, taxoids, vinca alkaloids (such as vinblastine andvincristine), epothilones (e.g. epothilone B), camptothecin and itsclinical analogs topotecan and irinotecan, or the like.

A “bioconjugate linker” is a covalent linker moiety that results frombioconjugate chemistry as generally known in the art. See for example,Bioconjugate Techniques, Second Edition, Greg T. Hermanson. Exemplarybioconjugate linkers can be found in Table 2 linking an adamantyl moiety(Ring A) to a variety of biomolecules, such as an antibody or peptide(e.g. modified peptide such as peptide including folate or a folatederivative).

In embodiments, a linker is formed by a conjugation or bioconjugationreaction combining a first reactant moiety covalently bonded to an agent(e.g., including R¹, a protein moiety, antibody moiety, siderophoremoiety, detectable moiety, or drug moiety) and a second reactant moietycovalently bonded to a linker of a compound described herein (e.g.,compound of formula I, Ia, Ib), for example a linker selected from L¹,L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, L⁹, L¹¹, L¹², L¹³, and L¹⁴. In suchembodiments, the compound formed by such conjugation or bioconjugationreaction (including compounds as described herein) may be referred to asa conjugate.

Conjugates described herein may be synthesized using bioconjugate orconjugate chemistry. Conjugate chemistry includes coupling two moleculestogether to form an adduct. Conjugation may be a covalent modification.Currently favored classes of conjugate chemistry reactions availablewith reactive known reactive groups are those which proceed underrelatively mild conditions. These include, but are not limited tonucleophilic substitutions (e.g., reactions of amines and alcohols withacyl halides, active esters), electrophilic substitutions (e.g., enaminereactions) and additions to carbon-carbon and carbon-heteroatom multiplebonds (e.g., Michael reaction, Diels-Alder addition). These and otheruseful reactions are discussed in, for example, March, ADVANCED ORGANICCHEMISTRY, 3rd Ed., John Wiley & Sons, New York, 1985; Hermanson,BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney etal., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol. 198,American Chemical Society, Washington, D.C., 1982, all of which areincorporated by reference in their entirety for all purposes. Inembodiments, the bioconjugation reaction is a click chemistry reaction(Angewandte Chemie International Edition 40 (11): 2004-2021). Inembodiments, the bioconjugation reaction is a Huisgen cyclization ofazides. In embodiments, the bioconjugation reaction is a coppercatalyzed Huisgen cyclization of azides. In embodiments, thebioconjugation reaction is a click chemistry reaction that does notrequire copper.

Useful reactive functional groups used for conjugate chemistries hereininclude, for example:

-   -   (a) carboxyl groups and various derivatives thereof including,        but not limited to, N-hydroxysuccinimide esters,        N-hydroxybenztriazole esters, acid halides, acyl imidazoles,        thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and        aromatic esters;    -   (b) hydroxyl groups which can be converted to esters, ethers,        aldehydes, etc.    -   (c) haloalkyl groups wherein the halide can be later displaced        with a nucleophilic group such as, for example, an amine, a        carboxylate anion, thiol anion, carbanion, or an alkoxide ion,        thereby resulting in the covalent attachment of a new group at        the site of the halogen atom;    -   (d) dienophile groups which are capable of participating in        Diels-Alder reactions such as, for example, maleimido groups;    -   (e) aldehyde or ketone groups such that subsequent        derivatization is possible via formation of carbonyl derivatives        such as, for example, imines, hydrazones, semicarbazones or        oximes, or via such mechanisms as Grignard addition or        alkyllithium addition;    -   (f) sulfonyl halide groups for subsequent reaction with amines,        for example, to form sulfonamides;    -   (g) thiol groups, which can be converted to disulfides, reacted        with acyl halides, or bonded to metals such as gold;    -   (h) amine or sulfhydryl groups, which can be, for example,        acylated, alkylated or oxidized;    -   (i) alkenes, which can undergo, for example, cycloadditions,        acylation, Michael addition, etc;    -   (j) epoxides, which can react with, for example, amines and        hydroxyl compounds;    -   (k) phosphoramidites and other standard functional groups useful        in nucleic acid synthesis;    -   (l) metal silicon oxide bonding; and    -   (m) metal bonding to reactive phosphorus groups (e.g.        phosphines) to form, for example, phosphate diester bonds.    -   (n) azides coupled to alkynes using copper catalyzed or        non-copper catalyzed cycloaddition click chemistry.

The reactive functional groups can be chosen such that they do notparticipate in, or interfere with, the chemical stability of theconjugate described herein. Alternatively, a reactive functional groupcan be protected from participating in the crosslinking reaction by thepresence of a protecting group.

“Chemotherapeutic” or “chemotherapeutic agent” is used in accordancewith its plain ordinary meaning and refers to a chemical composition orcompound having antineoplastic properties or the ability to inhibit thegrowth or proliferation of cells.

The terms “anti-infective agent” or “anti-infectious agent” or“anti-infective drug” or “anti-infective” are interchangeable and areused in accordance with their plain ordinary meaning and refer to acomposition (e.g. compound, drug, antagonist, inhibitor, modulator)having anti-infectious agent properties or the ability to inhibit thegrowth or proliferation of an infectious agent (e.g. parasite (e.g.protozoa), bacterium, virus, fungus, or microorganism) or treat asymptom of a disease caused by an infectious agent. In some embodiments,an anti-infective agent is an agent approved by the FDA or similarregulatory agency of a country other than the USA, for treatinginfection by an infectious agent or a disease associated with aninfectious agent. In embodiments, an anti-infective agent is an agentwith anti-infectious agent properties that has not (e.g., yet) beenapproved by the FDA or similar regulatory agency of a country other thanthe USA, for treating infection by an infectious agent or a diseaseassociated with an infectious agent. Examples of anti-infective agentsinclude, but are not limited to, anti-viral agents, anti-bacterialagents, antibiotics, anti-parasitic (e.g. anti-protozoan) agents,anti-malarial agents, and anti-fungal agents.

The terms “anti-bacterial agent” or “anti-bacterial drug” or“anti-bacterial” or “antibiotic” are interchangeable and are used inaccordance with their plain ordinary meaning and refer to a composition(e.g. compound, drug, antagonist, inhibitor, modulator) havinganti-bacterial properties or the ability to inhibit the growth orproliferation of bacteria (e.g., bacteria that infect humans). In someembodiments, an anti-bacterial agent is an agent approved by the FDA orsimilar regulatory agency of a country other than the USA, for treatinga bacterial infection. In embodiments, an anti-bacterial agent is anagent with the ability to inhibit the growth or proliferation ofbacteria that has not (e.g., yet) been approved by the FDA or similarregulatory agency of a country other than the USA, for treating abacterial infection. Examples of anti-bacterial agents include, but arenot limited to, Penicillins (e.g., penicillins, antistaphylococcalpenicillins, aminopenicillins, antipseudomonal penicillins),cephalosporins, polymyxins, rifamycins, lipiarmycins, quinolones,sulfonamides. macrolides, lincosamides, tetracyclines, aminoglycosides,cyclic lipopeptides (e.g., daptomycin, sufactin, echinocandins,caspofungin), glycylcyclines (e.g., tigecycline), oxazolidinones (e.g.,linezolid, posizolid, tedizolid, radezolid, cycloserine), lipiarmycins(e.g., fidaxomicin), mecillinams, and carbapenems. An anti-bacterialmoiety is a radical of an anti-bacterial. Non-limiting examples of ananti-bacterial agent include Amikacin, Gentamicin, Kanamycin, Neomycin,Netilmicin, Tobramycin, Paromomycin, Streptomycin, Spectinomycin,Geldanamycin, Herbimycin, Rifaximin, Loracarbef, Ertapenem, Doripenem,Imipenem/Cilastatin, Meropenem, Cefadroxil, Cefazolin, Cefalotin orCefalothin, Cefalexin, Cefaclor, Cefamandole, Cefoxitin, Cefprozil,Cefuroxime, Cefixime, Cefdinir, Cefditoren, Cefoperazone, Cefotaxime,Cefpodoxime, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone,Cefepime, Ceftaroline fosamil, Ceftobiprole, Teicoplanin, Vancomycin,Telavancin, Dalbavancin, Oritavancin, Clindamycin, Lincomycin,Daptomycin, Azithromycin, Clarithromycin, Dirithromycin, Erythromycin,Roxithromycin, Troleandomycin, Telithromycin, Spiramycin, Aztreonam,Furazolidone, Nitrofurantoin, Linezolid, Posizolid, Radezolid,Torezolid, Amoxicillin, Ampicillin, Azlocillin, Carbenicillin,Cloxacillin, Dicloxacillin, Flucloxacillin, Mezlocillin, Methicillin,Nafcillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin,Penicillin G, Temocillin, Ticarcillin, Amoxicillin/clavulanate,Ampicillin/sulbactam, Piperacillin/tazobactam, Ticarcillin/clavulanate,Bacitracin, Colistin, Polymyxin B, Ciprofloxacin, Enoxacin,Gatifloxacin, Gemifloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin,Nalidixic acid, Norfloxacin, Ofloxacin, Trovafloxacin, Grepafloxacin,Sparfloxacin, Temafloxacin, Mafenide, Sulfacetamide, Sulfadiazine,Silver sulfadiazine, Sulfadimethoxine, Sulfamethizole, Sulfamethoxazole,Sulfanilimide, Sulfasalazine, Sulfisoxazole,Trimethoprim-Sulfamethoxazole (Co-trimoxazole) (TMP-SMX),Sulfonamidochrysoidine, Demeclocycline, Doxycycline, Minocycline,Oxytetracycline, Tetracycline, Clofazimine, Dapsone, Capreomycin,Cycloserine, Ethambutol, Ethionamide, Isoniazid, Pyrazinamide,Rifampicin (Rifampin), Rifabutin, Rifapentine, Streptomycin,Arsphenamine, Chloramphenicol, Fosfomycin, Fusidic acid, Metronidazole,Mupirocin, Platensimycin, Quinupristin/Dalfopristin, Thiamphenicol,Tigecycline, Tinidazole, and Trimethoprim.

The terms “anti-malarial agent” or “anti-malarial drug” or“anti-malarial” are interchangeable and are used in accordance withtheir plain ordinary meaning and refer to a composition (e.g. compound,drug, antagonist, inhibitor, modulator) having anti-malarial propertiesor the ability to inhibit the growth or proliferation of Plasmodium thatinfect humans (e.g. P. vivax, P. ovale, P. malariae P. falciparum, P.knowlesi, P. brasilianum, P. cynomolgi, P. cynomolgi bastianellii, P.inui, P. rhodiani, P. schweitzi, P. semiovale, or P. simium). Inembodiments, an anti-malarial agent treats infection with P. vivax, P.ovale, P. malariae, and/or P. falciparum. In embodiments, ananti-malarial agent treats infection with P. vivax. In embodiments, ananti-malarial agent treats infection with P. ovale. In embodiments, ananti-malarial agent treats infection with P. malariae. In embodiments,an anti-malarial agent treats infection with P. falciparum. In someembodiments, an anti-malarial agent is an agent approved by the FDA orsimilar regulatory agency of a country other than the USA, for treatingmalaria. In embodiments, an anti-malarial agent is an agent with theability to inhibit the growth or proliferation of Plasmodium that infecthumans that has not (e.g., yet) been approved by the FDA or similarregulatory agency of a country other than the USA, for treating malaria.Examples of anti-malarial agents include, but are not limited to,amodiaquine, atovaquone, chloroquine, clardribine, clindamycin,cytarabine, daunorubicin, docetaxel, doxorubicin, doxycycline,etoposide, fansidar, fludarabine, halofantrine, idarubicin, imiquimod,irinotecan, mefloquine, methotrexate, mitomycin, oxamniquine,paclitaxel, plicamycin, primaquine, proquanil, pyrimethamine, quinidine,quinine, topotecan, vinblastine, vincristine, KA609, KAF 156,tafenoquine, and pyronaridine. An anti-malarial moiety is a radical ofan anti-malarial.

“Patient” or “subject in need thereof” or “subject” refers to a livingorganism suffering from or prone to a disease or condition that can betreated by administration of a compound or pharmaceutical composition orby a method, as provided herein. Non-limiting examples include humans,other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows,deer, and other non-mammalian animals. In some embodiments, a patient ishuman. In some embodiments, a subject is human.

“Disease” or “condition” refer to a state of being or health status of apatient or subject capable of being treated with a compound,pharmaceutical composition, or method provided herein. In someembodiments, the disease is a disease having the symptom of an increasedamount of Fe^(II) relative to normal Fe^(II) amounts in a subject (e.g.human). In some embodiments, the disease is a disease having the symptomof an increased amount of a reductant (e.g. biological reductant,Fe^(II)) relative to normal reductant (e.g. biological reductant,Fe^(II)) amounts in a subject (e.g. human). In embodiments, the diseaseis an infectious disease. In embodiments, the disease is a bacterialdisease. In embodiments, the disease is a parasitic disease. Inembodiments, the disease is a viral disease. In embodiments, the diseaseis malaria. In embodiments, the disease is drug-resistant malaria. Insome embodiments, the disease is a cancer. In some further instances,“cancer” refers to human cancers and carcinomas, sarcomas,adenocarcinomas, lymphomas, leukemias, etc., including solid andlymphoid cancers, kidney, breast, lung, bladder, colon, ovarian,prostate, pancreas, stomach, brain, head and neck, skin, uterine,testicular, glioma, esophagus, and liver cancer, includinghepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma,non-Hodgkin's lymphomas (e.g., Burkitt's, Small Cell, and Large Celllymphomas), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML),or multiple myeloma. In some embodiments, the disease is a diseaserelated to (e.g. caused by) an infectious agent (e.g. bacteria) Examplesof diseases, disorders, or conditions include, but are not limited to,infectious diseases, bacterial infectious diseases, nosocomialinfections, nosocomial bacterial infections, ventilator associatedpneumonias, bacterial blood stream infections, Cutaneous anthrax,Pulmonary anthrax, Gastrointestinal anthrax, Whooping cough, bacterialpneumonia, Lyme disease, Brucellosis, Acute enteritis,Community-acquired respiratory infection, Nongonococcal urethritis(NGU), Lymphogranuloma venereum (LGV), Trachoma, Inclusionconjunctivitis of the newborn (ICN), Psittacosis, Botulism,Pseudomembranous colitis, Gas gangrene, Acute food poisoning, Anaerobiccellulitis, Tetanus, Diphtheria, Nosocomial infections, Urinary tractinfections (UTI), Diarrhea, Meningitis in infants, Traveller's diarrhea,Diarrhea in infants, Hemorrhagic colitis, Hemolytic-uremic syndrome,Tularemia, Bacterial meningitis, Upper respiratory tract infections,Pneumonia, bronchitis, Peptic ulcer, gastric carcinoma, gastric B-celllymphoma, Legionnaire's Disease, Pontiac fever, Leptospirosis,Listeriosis, Leprosy (Hansen's disease), Tuberculosis, Mycoplasmapneumonia, Gonorrhea, Ophthalmia neonatorum, Septic arthritis,Meningococcal disease, Waterhouse-Friderichsen syndrome, Pseudomonasinfection, Bacteremia, endocarditis, Rocky mountain spotted fever,Typhoid fever type salmonellosis (dysentery, colitis), Salmonellosis,gastroenteritis, enterocolitis, Bacillary dysentery/Shigellosis,Coagulase-positive staphylococcal infections: Impetigo, Acute infectiveendocarditis, Septicemia, Necrotizing pneumonia, Toxinoses, Toxic shocksyndrome, Staphylococcal food poisoning, Cystitis, Meningitis,septicemia, Endometritis, Opportunistic infections, Acute bacterialpneumonia, Otitis media, sinusitis, Streptococcal pharyngitis, Scarletfever, Rheumatic fever, erysipelas, Puerperal fever, Necrotizingfasciitis, Syphilis, Congenital syphilis, Cholera, Plague, Bubonicplague, Pneumonic plague, sepsis, Iraq war infection caused byAcinetobacter baumannii (i.e. Iraq war-related Acinetobacter baumanniiinfection), skin diseases or conditions, acne, acne vulgaris, keratosispilaris, acne rosacea, harlequin ichthyosis, xeroderma pigmentosum,keratoses, eczema, rosacea, necrotizing fasciitis, tuberculosis,hospital-acquired pneumonia, gastroenteritis, or bacteremia.

As used herein, the term “infectious disease” refers to a disease orcondition related to the presence of an organism (the agent orinfectious agent) within or contacting the subject or patient. Examplesinclude a bacterium, fungus, virus, or other microorganism. A “bacterialinfectious disease” or “bacterial disease” is an infectious diseasewherein the organism is a bacterium. A “viral infectious disease” or“viral disease” is an infectious disease wherein the organism is avirus. An “antibiotic resistant bacterial infectious disease” or“antibiotic resistant bacterial disease” is an infectious diseasewherein the organism is a bacterium resistant to one or more antibioticseffective in treating a disease caused by the non-antibiotic resistantstrains of the bacterium. A “penicillin resistant bacterial infectiousdisease” or “penicillin resistant bacterial disease” is an antibioticresistant bacterial infectious disease wherein the disease is nottreated as effectively by a penicillin or penicillin-related compoundsas a similar disease caused by a bacterial strain that is not penicillinresistant. A “cephalosporin resistant bacterial infectious disease” or“cephalosporin resistant bacterial disease” is an antibiotic resistantbacterial infectious disease wherein the disease is not treated aseffectively by a cephalosporin or cephalosporin-related compounds as asimilar disease caused by a bacterial strain that is not cephalosporinresistant. A “beta-lactam antibiotic resistant bacterial infectiousdisease” or “beta-lactam antibiotic resistant bacterial disease” is a anantibiotic resistant bacterial infectious disease wherein the disease isnot treated as effectively by beta-lactam containing antibiotics as asimilar disease caused by a bacterial strain that is not beta-lactamantibiotic resistant. Examples of infectious diseases that may betreated with a compound or method described herein include nosocomialinfections, bacteremia, Cutaneous anthrax, Pulmonary anthrax,Gastrointestinal anthrax, Whooping cough, bacterial pneumonia,bacteremia, Lyme disease, Brucellosis, Acute enteritis,Community-acquired respiratory infection, Nongonococcal urethritis(NGU), Lymphogranuloma venereum (LGV), Trachoma, Inclusionconjunctivitis of the newborn (ICN), Psittacosis, Botulism,Pseudomembranous colitis, Gas gangrene, Acute food poisoning, Anaerobiccellulitis, Tetanus, Diphtheria, Nosocomial infections, Urinary tractinfections (UTI), Diarrhea, Meningitis in infants, Traveller's diarrhea,Diarrhea in infants, Hemorrhagic colitis, Hemolytic-uremic syndrome,Tularemia, Bacterial meningitis, Upper respiratory tract infections,Pneumonia, bronchitis, Peptic ulcer, gastric carcinoma, gastric B-celllymphoma, Legionnaire's Disease, Pontiac fever, Leptospirosis,Listeriosis, Leprosy (Hansen's disease), Tuberculosis, Mycoplasmapneumonia, Gonorrhea, Ophthalmia neonatorum, Septic arthritis,Meningococcal disease, Waterhouse-Friderichsen syndrome, Pseudomonasinfection, Bacteremia, endocarditis, Rocky mountain spotted fever,Typhoid fever type salmonellosis (dysentery, colitis), Salmonellosis,gastroenteritis, enterocolitis, Bacillary dysentery/Shigellosis,Coagulase-positive staphylococcal infections: Impetigo, Acute infectiveendocarditis, Septicemia, Necrotizing pneumonia, Toxinoses, Toxic shocksyndrome, Staphylococcal food poisoning, Cystitis, Meningitis,septicemia, Endometritis, Opportunistic infections, Acute bacterialpneumonia, Otitis media, sinusitis, Streptococcal pharyngitis, Scarletfever, Rheumatic fever, erysipelas, Puerperal fever, Necrotizingfasciitis, Syphilis, Congenital syphilis, Cholera, Plague, Bubonicplague, Pneumonic plague, Iraq war infection caused by Acinetobacterbaumannii (i.e. Iraq war-related Acinetobacter baumannii infection),necrotizing fasciitis, tuberculosis, hospital-acquired pneumonia,gastroenteritis, or sepsis.

“Infectious agent” refers to an organism that is associated with (in orcontacting) patients with an infectious disease but not in patientswithout the infectious disease and wherein contacting a patient withoutthe infectious disease with the organism results in the patient havingthe infectious disease. In some embodiments, the infectious agentassociated with a disease that may be treated by the compounds and/ormethods described herein is a bacterium. In some embodiments, thebacteria is of a genera selected from Stenotrophomonas, Clostridium,Acinetobacter, Bordetella, Borrelia, Brucella, Campylobacter, Chlamydia,Chlamydophila, Clostridium, Corynebacterium, Enterococcus, Escherichia,Francisella, Haemophilus, Helicobacter, Legionella, Leptospira,Listeria, Mycobacterium, Mycoplasma, Neisseria, Pseudomonas, Rickettsia,Salmonella, Shigella, Staphylococcus, Streptococcus, Treponema, Vibrio,Klebsiella, Enterobacter, Citrobacter, or Yersinia. In some embodiments,the bacteria is selected from Stenotrophomonas maltophilia, Clostridiumdifficile, Bacillus anthracis, Bordetella pertussis, Borreliaburgdorferi, Brucella abortus, Brucella canis, Brucella melitensis,Brucella suis, Campylobacter jejuni, Chlamydia pneumoniae, Chlamydiatrachomatis, Chlamydophila psittaci, Clostridium botulinum, Clostridiumdifficile, Clostridium perfringens, Clostridium tetani, Corynebacteriumdiphtheriae, Enterococcus faecalis, Enterococcus faecium, Escherichiacoli, Enterotoxigenic Escherichia coli (ETEC), Enteropathogenic E. coli,E. coli O157:H7, Francisella tularensis, Haemophilus influenzae,Helicobacter pylori, Legionella pneumophila, Leptospira interrogans,Listeria monocytogenes, Mycobacterium leprae, Mycobacteriumtuberculosis, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseriameningitidis, Pseudomonas aeruginosa, Rickettsia rickettsii, Salmonellatyphi, Salmonella typhimurium, Shigella sonnei, Staphylococcus aureus,Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcusagalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, Treponemapallidum, Vibrio cholerae, Klebsiella pneumoniae, Enterobacter cloacae,Citrobacter freundii, Acinetobacter baumannii, or Yersinia pestis. Insome embodiments, the bacteria is gram negative. In some embodiments,the bacteria is gram positive.

As used herein, the term “cancer” refers to all types of cancer,neoplasm or malignant tumors found in mammals (e.g. humans), includingleukemia, carcinomas and sarcomas. Exemplary cancers that may be treatedwith a compound or method provided herein include cancer of the thyroid,endocrine system, brain, breast, cervix, colon, head & neck, liver,kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary,sarcoma, stomach, uterus, Medulloblastoma, colorectal cancer, pancreaticcancer. Additional examples may include, Hodgkin's Disease,Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma,glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primarythrombocytosis, primary macroglobulinemia, primary brain tumors, cancer,malignant pancreatic insulanoma, malignant carcinoid, urinary bladdercancer, premalignant skin lesions, testicular cancer, lymphomas, thyroidcancer, neuroblastoma, esophageal cancer, genitourinary tract cancer,malignant hypercalcemia, endometrial cancer, adrenal cortical cancer,neoplasms of the endocrine or exocrine pancreas, medullary thyroidcancer, medullary thyroid carcinoma, melanoma, colorectal cancer,papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

The term “leukemia” refers broadly to progressive, malignant diseases ofthe blood-forming organs and is generally characterized by a distortedproliferation and development of leukocytes and their precursors in theblood and bone marrow. Leukemia is generally clinically classified onthe basis of (1) the duration and character of the disease-acute orchronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid(lymphogenous), or monocytic; and (3) the increase or non-increase inthe number abnormal cells in the blood-leukemic or aleukemic(subleukemic). Exemplary leukemias that may be treated with a compoundor method provided herein include, for example, acute nonlymphocyticleukemia, chronic lymphocytic leukemia, acute granulocytic leukemia,chronic granulocytic leukemia, acute promyelocytic leukemia, adultT-cell leukemia, aleukemic leukemia, a leukocythemic leukemia,basophylic leukemia, blast cell leukemia, bovine leukemia, chronicmyelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilicleukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia,hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia,acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia,lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia,lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia,megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia,myeloblastic leukemia, myelocytic leukemia, myeloid granulocyticleukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cellleukemia, multiple myeloma, plasmacytic leukemia, promyelocyticleukemia, Rieder cell leukemia, Schilling's leukemia, stem cellleukemia, subleukemic leukemia, or undifferentiated cell leukemia.

The term “sarcoma” generally refers to a tumor which is made up of asubstance like the embryonic connective tissue and is generally composedof closely packed cells embedded in a fibrillar or homogeneoussubstance. Sarcomas that may be treated with a compound or methodprovided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma,melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adiposesarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma,botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma,Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing'ssarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma,granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmentedhemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma,immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma,Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymomasarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma,serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

The term “melanoma” is taken to mean a tumor arising from themelanocytic system of the skin and other organs. Melanomas that may betreated with a compound or method provided herein include, for example,acral-lentiginous melanoma, amelanotic melanoma, benign juvenilemelanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma,juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodularmelanoma, subungal melanoma, or superficial spreading melanoma.

The term “carcinoma” refers to a malignant new growth made up ofepithelial cells tending to infiltrate the surrounding tissues and giverise to metastases. Exemplary carcinomas that may be treated with acompound or method provided herein include, for example, medullarythyroid carcinoma, familial medullary thyroid carcinoma, acinarcarcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cysticcarcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolarcarcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinomabasocellulare, basaloid carcinoma, basosquamous cell carcinoma,bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogeniccarcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorioniccarcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma,cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum,cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma,carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoidcarcinoma, carcinoma epitheliale adenoides, exophytic carcinoma,carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma,gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare,glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma,hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma,hyaline carcinoma, hypernephroid carcinoma, infantile embryonalcarcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelialcarcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cellcarcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatouscarcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullarycarcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma,carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma,carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes,nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans,osteoid carcinoma, papillary carcinoma, periportal carcinoma,preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma,renal cell carcinoma of kidney, reserve cell carcinoma, carcinomasarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinomascroti, signet-ring cell carcinoma, carcinoma simplex, small-cellcarcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cellcarcinoma, carcinoma spongiosum, squamous carcinoma, squamous cellcarcinoma, string carcinoma, carcinoma telangiectaticum, carcinomatelangiectodes, transitional cell carcinoma, carcinoma tuberosum,tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.

The term “signaling pathway” as used herein refers to a series ofinteractions between cellular and optionally extra-cellular components(e.g. proteins, nucleic acids, small molecules, ions, lipids) thatconveys a change in one component to one or more other components, whichin turn may convey a change to additional components, which isoptionally propagated to other signaling pathway components.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the administration of an activeagent to and absorption by a subject and can be included in thecompositions of the present invention without causing a significantadverse toxicological effect on the patient. Non-limiting examples ofpharmaceutically acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors, salt solutions (such as Ringer's solution), alcohols, oils,gelatins, carbohydrates such as lactose, amylose or starch, fatty acidesters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, andthe like. Such preparations can be sterilized and, if desired, mixedwith auxiliary agents such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressure,buffers, coloring, and/or aromatic substances and the like that do notdeleteriously react with the compounds of the invention. One of skill inthe art will recognize that other pharmaceutical excipients are usefulin the present invention.

The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

As used herein, the term “administering” means oral administration,administration as a suppository, topical contact, intravenous,parenteral, intraperitoneal, intramuscular, intralesional, intrathecal,intracranial, intranasal or subcutaneous administration, or theimplantation of a slow-release device, e.g., a mini-osmotic pump, to asubject. Administration is by any route, including parenteral andtransmucosal (e.g., buccal, sublingual, palatal, gingival, nasal,vaginal, rectal, or transdermal). Parenteral administration includes,e.g., intravenous, intramuscular, intra-arteriole, intradermal,subcutaneous, intraperitoneal, intraventricular, and intracranial. Othermodes of delivery include, but are not limited to, the use of liposomalformulations, intravenous infusion, transdermal patches, etc. By“co-administer” it is meant that a composition described herein isadministered at the same time, just prior to, or just after theadministration of one or more additional therapies (e.g. anti-canceragent, anti-infective, anti-bacterial, anti-parasitic, anti-malarial).The compound of the invention can be administered alone or can becoadministered to the patient. Coadministration is meant to includesimultaneous or sequential administration of the compound individuallyor in combination (more than one compound or agent). Thus, thepreparations can also be combined, when desired, with other activesubstances (e.g. to reduce metabolic degradation, to increasedegradation of a prodrug and release of the drug, detectable agent,protein). The compositions of the present invention can be delivered bytransdermally, by a topical route, formulated as applicator sticks,solutions, suspensions, emulsions, gels, creams, ointments, pastes,jellies, paints, powders, and aerosols. Oral preparations includetablets, pills, powder, dragees, capsules, liquids, lozenges, cachets,gels, syrups, slurries, suspensions, etc., suitable for ingestion by thepatient. Solid form preparations include powders, tablets, pills,capsules, cachets, suppositories, and dispersible granules. Liquid formpreparations include solutions, suspensions, and emulsions, for example,water or water/propylene glycol solutions. The compositions of thepresent invention may additionally include components to providesustained release and/or comfort. Such components include high molecularweight, anionic mucomimetic polymers, gelling polysaccharides andfinely-divided drug carrier substrates. These components are discussedin greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and4,861,760. The entire contents of these patents are incorporated hereinby reference in their entirety for all purposes. The compositions of thepresent invention can also be delivered as microspheres for slow releasein the body. For example, microspheres can be administered viaintradermal injection of drug-containing microspheres, which slowlyrelease subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645,1995; as biodegradable and injectable gel formulations (see, e.g., GaoPharm. Res. 12:857-863, 1995); or, as microspheres for oraladministration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674,1997). In another embodiment, the formulations of the compositions ofthe present invention can be delivered by the use of liposomes whichfuse with the cellular membrane or are endocytosed, i.e., by employingreceptor ligands attached to the liposome, that bind to surface membraneprotein receptors of the cell resulting in endocytosis. By usingliposomes, particularly where the liposome surface carries receptorligands specific for target cells, or are otherwise preferentiallydirected to a specific organ, one can focus the delivery of thecompositions of the present invention into the target cells in vivo.(See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn,Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm.46:1576-1587, 1989). The compositions of the present invention can alsobe delivered as nanoparticles.

Pharmaceutical compositions provided by the present invention includecompositions wherein the active ingredient (e.g. compounds describedherein, including embodiments or examples) is contained in atherapeutically effective amount, i.e., in an amount effective toachieve its intended purpose. The actual amount effective for aparticular application will depend, inter alia, on the condition beingtreated. When administered in methods to treat a disease, suchcompositions will contain an amount of active ingredient effective toachieve the desired result, e.g., reducing, eliminating, or slowing theprogression of disease symptoms (e.g. symptoms of cancer, an infectiousdisease, or malaria). Determination of a therapeutically effectiveamount of a compound of the invention is well within the capabilities ofthose skilled in the art, especially in light of the detailed disclosureherein.

The dosage and frequency (single or multiple doses) administered to amammal can vary depending upon a variety of factors, for example,whether the mammal suffers from another disease, and its route ofadministration; size, age, sex, health, body weight, body mass index,and diet of the recipient; nature and extent of symptoms of the diseasebeing treated (e.g. symptoms of cancer, an infectious disease, ormalaria), kind of concurrent treatment, complications from the diseasebeing treated or other health-related problems. Other therapeuticregimens or agents can be used in conjunction with the methods andcompounds of Applicants' invention. Adjustment and manipulation ofestablished dosages (e.g., frequency and duration) are well within theability of those skilled in the art.

For any compound described herein, the therapeutically effective amountcan be initially determined from cell culture assays. Targetconcentrations will be those concentrations of active compound(s) thatare capable of achieving the methods described herein, as measured usingthe methods described herein or known in the art.

As is well known in the art, therapeutically effective amounts for usein humans can also be determined from animal models. For example, a dosefor humans can be formulated to achieve a concentration that has beenfound to be effective in animals. The dosage in humans can be adjustedby monitoring compounds effectiveness and adjusting the dosage upwardsor downwards, as described above. Adjusting the dose to achieve maximalefficacy in humans based on the methods described above and othermethods is well within the capabilities of the ordinarily skilledartisan.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the present invention should be sufficient to effect abeneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side-effects. Determination of the proper dosage for aparticular situation is within the skill of the practitioner. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under circumstances isreached.

Dosage amounts and intervals can be adjusted individually to providelevels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

Utilizing the teachings provided herein, an effective prophylactic ortherapeutic treatment regimen can be planned that does not causesubstantial toxicity and yet is effective to treat the clinical symptomsdemonstrated by the particular patient. This planning should involve thecareful choice of active compound by considering factors such ascompound potency, relative bioavailability, patient body weight,presence and severity of adverse side effects, preferred mode ofadministration and the toxicity profile of the selected agent.

The compounds described herein can be used in combination with oneanother, with other active agents known to be useful in treating cancer,or with adjunctive agents that may not be effective alone, but maycontribute to the efficacy of the active agent.

In some embodiments, co-administration includes administering one activeagent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a secondactive agent. Co-administration includes administering two active agentssimultaneously, approximately simultaneously (e.g., within about 1, 5,10, 15, 20, or 30 minutes of each other), or sequentially in any order.In some embodiments, co-administration can be accomplished byco-formulation, i.e., preparing a single pharmaceutical compositionincluding both active agents. In other embodiments, the active agentscan be formulated separately. In another embodiment, the active and/oradjunctive agents may be linked or conjugated to one another. In someembodiments, the compounds described herein may be combined withtreatments for cancer such as radiation or surgery.

B. Compounds

In an aspect is provided a compound, or a pharmaceutically acceptablesalt thereof, having the formula:

wherein L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, L⁹, L¹¹, and L¹² are independently abond, —N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)O-L¹³-L¹⁴-, —O-L¹³-L¹⁴-, —S-L¹³-L¹⁴-,—OC(O)-L¹³-L¹⁴-, —OC(O)N(R¹⁷)-L¹³-L¹⁴-, —OC(O)O-L¹³-L¹⁴-,—OSO₂-L¹³-L¹⁴-, —C(O)N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)-L¹³-L¹⁴-,—S(O)₂N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)S(O)₂-L¹³-L¹⁴-, substituted orunsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene, or a bioconjugate linker(e.g. where R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹, and R¹² is, for examplea biomolecule such as a protein moiety (e.g antibody moiety, peptidemoiety, modified peptide moiety such as peptide moiety includingfolate). L¹⁰ is —N(-L¹¹-R¹¹)— or —C((-L¹¹-R¹¹)(-L¹²-R¹²))—. Each L¹³ andL¹⁴ are independently selected from a bond, —N(R¹⁷)—, —N(R¹⁷)C(O)O—,—O—, —S—, —OC(O)—, —OC(O)N(R¹⁷)—, —OC(O)O—, —OSO₂—, —C(O)N(R¹⁷)—,—N(R¹⁷)C(O)—, —S(O)₂N(R¹⁷)—, —N(R¹⁷)S(O)₂—, substituted or unsubstitutedalkylene, substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, substitutedor unsubstituted heteroarylene, or a bioconjugate linker (e.g. where R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹, and R¹² is, for example a biomoleculesuch as a protein moiety (e.g antibody, peptide, modified peptide suchas peptide including folate). R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹, andR¹², are independently hydrogen, oxo, halogen, —CX₃, —CN, —SO₂Cl,—SO_(n)R¹⁶, —SO_(v)NR¹³R¹⁴, —NHNH₂, —ONR¹³R¹⁴, —NHC═(O)NHNH₂,—NHC═(O)NR¹³R¹⁴, —N(O)_(m), —NR¹³R¹⁴, —C(O)R¹⁵, —C(O)—OR¹⁵,—C(O)NR¹³R¹⁴, —OR¹⁶, —NR¹³SO₂R¹⁶, —NR¹³C═(O)R¹⁵, —NR¹³C(O)—OR¹⁵,—NR¹³OR¹⁵, —OCX₃, —OCHX₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, aprotein moiety, a detectable moiety, or a drug moiety; R⁵ and R¹¹substituents may be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁶and R¹¹ substituents may be joined to form a substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R² and R³, R⁴ and R⁵, R⁶ and R⁷, R⁸ and R⁹, or R¹¹ and R¹²may be joined to form a substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. EachR¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are independently hydrogen, halogen, —CF₃,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹³and R¹⁴ substituents bonded to the same atom may be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl. R¹⁸ and R¹⁹ are independently hydrogen,halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, a protein moiety, detectable moiety,siderophore moiety, or a drug moiety; R¹⁸ and R¹⁹ may be joined to forma substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, protein moiety, detectable moiety, or drug moiety. Thesymbols m and v are independently 1 or 2. The symbol n is independentlyan integer from 0 to 2. Y is —O—, —S—, —OO—, —CH₂O—, or —OCH₂—. X isindependently —Cl, —Br, —I, or —F.

The compounds described herein (e.g. formulae I, Ia, Ib, and embodimentsthereof) are prodrugs. The term “compound” when referring to a compoundof the invention and the term “prodrug” when referring to a prodrug ofthe invention (e.g. compound including a drug moiety or those compoundsincluding a detectable moiety, protein moiety, or other moiety in placeof a drug moiety or in addition to a drug moiety) are interchangeable.In embodiments, the compounds described herein (e.g. formula I and/orembodiments thereof) are prodrugs, wherein the prodrug moiety is thecomponent of the compound that is not a drug moiety/detectablemoiety/protein moiety and is released from the drug moiety/detectablemoiety/protein moiety upon degradation of the prodrug in the presence ofa high level of reductant (e.g. biological reductant, Fe^(II)). Inembodiments, degradation of the prodrug in the presence of a high levelof reductant (e.g. biological reductant, Fe^(II)) includes opening ofthe peroxide containing ring (e.g. trioxolane) in the prodrug moiety andrelease of an active drug/detectable agent/protein (e.g. where themonovalent moiety is cleaved to form a compound with full valency). Aperson having ordinary skill in the art would understand that thedrug/detectable agent/protein and drug moiety/detectable moiety/proteinmoiety include only those compounds compatible with the chemistryprovided herein for connecting the drug moiety/detectable moiety/proteinmoiety to the prodrug moiety and for release of the drug/detectableagent/protein from the compound (prodrug) by the presence of a highlevel of reductant (e.g. biological reductant, Fe^(II)). In embodiments,degradation of the prodrug to release an active agent (e.g., drug,protein, detectable agent, active compound) may result in an activeagent including a linker or portion of the peroxide containing ring inthe active agent. In such compounds, the resulting active agent includesa higher level of activity compared to the level of activity of theintact prodrug.

In embodiments, a drug moiety is i) a radical composition that uponrelease (cleavage of the bond connecting the drug moiety to the prodrugmoiety) from a compound (i.e. prodrugs) described herein, forms a drug(e.g. therapeutic agent); and ii) is connected to the prodrug moiety bya bond to an N atom of the drug moiety. In embodiments, a drug moiety isi) a radical composition that upon release (cleavage of the bondconnecting the drug moiety to the prodrug moiety) from a compound (i.e.prodrugs) described herein, forms a drug (e.g. therapeutic agent); andii) is connected to the prodrug moiety by a bond to an O atom of thedrug moiety. In embodiments, a drug moiety is i) a radical compositionthat upon release (cleavage of the bond connecting the drug moiety tothe prodrug moiety) from a compound (i.e. prodrugs) described herein,forms a drug (e.g. therapeutic agent); and ii) is connected to theprodrug moiety by a bond to an S atom of the drug moiety. Inembodiments, a drug moiety is i) a radical composition that upon release(cleavage of the bond connecting the drug moiety to the prodrug moiety)from a compound (i.e. prodrugs) described herein, forms a drug (e.g.therapeutic agent); and ii) is connected to the prodrug moiety by a bondto a —OC(O)-(remainder of drug moiety) of the drug moiety. Inembodiments, the drug moiety is an anti-cancer agent moiety (e.g.,described herein). In embodiments, the drug moiety is an anti-infectiveagent moiety (e.g., described herein). In embodiments, the drug moietyis an anti-malaria agent moiety (e.g., described herein). Inembodiments, the drug moiety is an anti-bacterial agent moiety (e.g.,described herein). In embodiments, the drug moiety is an antibioticmoiety (e.g., described herein). In embodiments, the drug moiety is ananti-parasitic agent moiety (e.g., described herein).

In embodiments, a detectable moiety is i) a radical composition thatupon release (cleavage of the bond connecting the detectable moiety tothe prodrug moiety) from a compound (i.e. prodrugs) described herein,forms a detectable agent (e.g. fluorescent agent); and ii) is connectedto the prodrug moiety by a bond to an N atom of the detectable moiety.In embodiments, a detectable moiety is i) a radical composition thatupon release (cleavage of the bond connecting the detectable moiety tothe prodrug moiety) from a compound (i.e. prodrugs) described herein,forms a detectable agent (e.g. fluorescent agent); and ii) is connectedto the prodrug moiety by a bond to an O atom of the detectable moiety.In embodiments, a detectable moiety is i) a radical composition thatupon release (cleavage of the bond connecting the detectable moiety tothe prodrug moiety) from a compound (i.e. prodrugs) described herein,forms a detectable agent (e.g. fluorescent agent); and ii) is connectedto the prodrug moiety by a bond to an S atom of the detectable moiety.In embodiments, a drug moiety is i) a radical composition that uponrelease (cleavage of the bond connecting the drug moiety to the prodrugmoiety) from a compound (i.e. prodrugs) described herein, forms a drug(e.g. therapeutic agent); and ii) is connected to the prodrug moiety bya bond to a —OC(O)-(remainder of detectable moiety) of the detectablemoiety.

In embodiments, a protein moiety is i) a radical composition that uponrelease (cleavage of the bond connecting the protein moiety to theprodrug moiety) from a compound (i.e. prodrugs) described herein, formsa protein (e.g antibody); and ii) is connected to the prodrug moiety bya bond to an N atom of the protein moiety. In embodiments, a proteinmoiety is i) a radical composition that upon release (cleavage of thebond connecting the protein moiety to the prodrug moiety) from acompound (i.e. prodrugs) described herein, forms a protein (e.gantibody); and ii) is connected to the prodrug moiety by a bond to an Oatom of the protein moiety. In embodiments, a protein moiety is i) aradical composition that upon release (cleavage of the bond connectingthe protein moiety to the prodrug moiety) from a compound (i.e.prodrugs) described herein, forms a protein (e.g antibody); and ii) isconnected to the prodrug moiety by a bond to an S atom of the proteinmoiety. In embodiments, a drug moiety is i) a radical composition thatupon release (cleavage of the bond connecting the drug moiety to theprodrug moiety) from a compound (i.e. prodrugs) described herein, formsa drug (e.g. therapeutic agent); and ii) is connected to the prodrugmoiety by a bond to a —OC(O)-(remainder of protein moiety) of theprotein moiety.

In embodiments, Y is —O—. In embodiments, Y is —S—. In embodiments, Y is—OO—. In embodiments, Y is —CH₂O—. In embodiments, Y is —OCH₂—. Inembodiments, R¹⁷ is independently hydrogen. In embodiments, L¹⁰ is—N(-L¹¹-R¹¹)—. In embodiments, L¹⁰ is —C((-L¹¹-R¹¹)(-L¹²-R¹²))—. Inembodiments, m is independently 1. In embodiments, m is independently 2.In embodiments, v is independently 1. In embodiments, v is independently2. In embodiments, n is independently 0. In embodiments, n isindependently 1. In embodiments, n is independently 2. In embodiments, Xis independently —Cl. In embodiments, X is independently —Br. Inembodiments, X is independently —I. In embodiments, X is independently—F. In embodiments, R² and R³, R⁴ and R⁵, R⁶ and R⁷, R⁸ and R⁹, or R¹¹and R¹² may be joined to form a substituted or unsubstituted cycloalkylor substituted or unsubstituted heterocycloalkyl.

In embodiments, R⁴ is a protein moiety. In embodiments, R⁴ is a drugmoiety. In embodiments, R⁴ is a detectable moiety. In embodiments, R⁵ isa protein moiety. In embodiments, R⁵ is a drug moiety. In embodiments,R⁵ is a detectable moiety. In embodiments, R⁶ is a protein moiety. Inembodiments, R⁶ is a drug moiety. In embodiments, R⁶ is a detectablemoiety. In embodiments, R⁷ is a protein moiety. In embodiments, R⁷ is adrug moiety. In embodiments, R⁷ is a detectable moiety. In embodiments,R¹¹ is a protein moiety. In embodiments, R¹¹ is a drug moiety. Inembodiments, R¹¹ is a detectable moiety. In embodiments, R¹² is aprotein moiety. In embodiments, R¹² is a drug moiety. In embodiments,R¹² is a detectable moiety. In embodiments, R² is a protein moiety. Inembodiments, R² is a drug moiety. In embodiments, R² is a detectablemoiety. In embodiments, R³ is a protein moiety. In embodiments, R³ is adrug moiety. In embodiments, R³ is a detectable moiety. In embodiments,R⁸ is a protein moiety. In embodiments, R⁸ is a drug moiety. Inembodiments, R⁸ is a detectable moiety. In embodiments, R⁹ is a proteinmoiety. In embodiments, R⁹ is a drug moiety. In embodiments, R⁹ is adetectable moiety. In embodiments, R² is an antibody moiety. Inembodiments, R³ is an antibody moiety. In embodiments, R⁴ is an antibodymoiety. In embodiments, R⁵ is an antibody moiety. In embodiments, R⁶ isan antibody moiety. In embodiments, R⁷ is an antibody moiety. Inembodiments, R⁸ is an antibody moiety. In embodiments, R⁹ is an antibodymoiety. In embodiments, R¹¹ is an antibody moiety. In embodiments, R¹²is an antibody moiety. In embodiments, R² is a siderophore moiety. Inembodiments, R³ is a siderophore moiety. In embodiments, R⁴ is asiderophore moiety. In embodiments, R⁵ is a siderophore moiety. Inembodiments, R⁶ is a siderophore moiety. In embodiments, R⁷ is asiderophore moiety. In embodiments, R⁸ is a siderophore moiety. Inembodiments, R⁹ is a siderophore moiety. In embodiments, R¹¹ is asiderophore moiety. In embodiments, R¹² is a siderophore moiety.

In embodiments, a compound described herein (prodrug described herein)including a drug moiety is less active than the corresponding free drug.In embodiments, a compound described herein does not have the activityof the free drug. In embodiments, a compound described herein has lessthan 0.9 times the activity of the free drug (e.g. less than 0.8, 0.7,0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03,0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, or0.001 times the activity of the free drug). Drug moieties that form partof the prodrugs described herein may obtain functionality due tochemical changes in the prodrugs that occur under physiologicalconditions.

In embodiments, a compound described herein (prodrug described herein)including a detectable moiety is less detectable than the correspondingfree detectable agent. In embodiments, a prodrug compound including adetectable moiety described herein cannot be detected using an identicalmethod capable of detecting the free detectable agent. In embodiments, aprodrug compound including a detectable moiety described herein is lessthan 0.9 times as detectable as the free detectable moiety (e.g. lessthan 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06,0.05, 0.04, 0.03, 0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004,0.003, 0.002, or 0.001 times as detectable as the free detectable moietyusing the same method (e.g. assay)). In embodiments, a prodrug compoundincluding a detectable moiety described herein is at least 0.9 times asdetectable as the free detectable moiety (e.g. at least 0.8, 0.7, 0.6,0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02,0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, or 0.001times as detectable as the free detectable moiety using the same method(e.g. assay)). In embodiments, a compound described herein can bedetected with the same sensitivity as the free detectable agent using anidentical method of detection.

In embodiments, a compound described herein includes one drug moiety. Inembodiments, a compound described herein includes a plurality ofoptionally different drug moieties. In embodiments, a compound describedherein includes one detectable moiety. In embodiments, a compounddescribed herein includes a plurality of optionally different detectablemoieties. In embodiments, a compound described herein includes oneprotein moiety. In embodiments, a compound described herein includes aplurality of optionally different protein moieties. In embodiments, acompound described herein includes at least one drug moiety and at leastone detectable moiety. In embodiments, a compound described hereinincludes at least one drug moiety and at least one protein moiety. Inembodiments, a compound described herein includes at least one proteinmoiety and at least one detectable moiety. In embodiments, a compounddescribed herein includes at least one protein moiety, at least one drugmoiety, and at least one detectable moiety. In embodiments, a compounddescribed herein includes one antibody moiety. In embodiments, acompound described herein includes a plurality of optionally differentantibody moieties. In embodiments, a compound described herein includesone siderophore moiety. In embodiments, a compound described hereinincludes a plurality of optionally different siderophore moieties.

In embodiments L² is a bond. In embodiments L² is —OC(O)—. Inembodiments L² is —OC(O)NH-Ph-CH₂—. In embodiments L² is—OC(O)NH-Ph-CH₂—OC(O)—. In embodiments L² is —NH-Ph-CH₂—. In embodimentsL² is —NH-Ph-CH₂—OC(O)—. In embodiments L² is —O-Ph-CH₂—. In embodimentsL² is —O-Ph-CH₂—OC(O)—. In embodiment, R² is a protein moiety. Inembodiment, R² is a protein moiety bonded to L² through an N of theprotein moiety. In embodiment, R² is a protein moiety bonded to L²through an O of the protein moiety. In embodiment, R² is a proteinmoiety bonded to L² through an S of the protein moiety. In embodiment,R² is a protein moiety bonded to L² through an O of a —OC(O)— of theprotein moiety. In embodiment, R² is a detectable moiety. In embodiment,R² is a detectable moiety bonded to L² through an N of the detectablemoiety. In embodiment, R² is a detectable moiety bonded to L² through anO of the detectable moiety. In embodiment, R² is a detectable moietybonded to L² through an S of the detectable moiety. In embodiment, R² isa detectable moiety bonded to L² through an O of a —OC(O)— of thedetectable moiety. In embodiment, R² is a drug moiety. In embodiment, R²is a drug moiety bonded to L² through an N of the drug moiety. Inembodiment, R² is a drug moiety bonded to L² through an O of the drugmoiety. In embodiment, R² is a drug moiety bonded to L² through an S ofthe drug moiety. In embodiment, R² is a drug moiety bonded to L² throughan O of a —OC(O)— of the drug moiety.

In embodiments L³ is a bond. In embodiments L³ is —OC(O)—. Inembodiments L³ is —OC(O)NH-Ph-CH₂—. In embodiments L³ is—OC(O)NH-Ph-CH₂—OC(O)—. In embodiments L³ is —NH-Ph-CH₂—. In embodimentsL³ is —NH-Ph-CH₂—OC(O)—. In embodiments L³ is —O-Ph-CH₂-. In embodimentsL³ is —O-Ph-CH₂—OC(O)—. In embodiment, R³ is a protein moiety. Inembodiment, R³ is a protein moiety bonded to L³ through an N of theprotein moiety. In embodiment, R³ is a protein moiety bonded to L³through an O of the protein moiety. In embodiment, R³ is a proteinmoiety bonded to L³ through an S of the protein moiety. In embodiment,R³ is a protein moiety bonded to L³ through an O of a —OC(O)— of theprotein moiety. In embodiment, R³ is a detectable moiety. In embodiment,R³ is a detectable moiety bonded to L³ through an N of the detectablemoiety. In embodiment, R³ is a detectable moiety bonded to L³ through anO of the detectable moiety. In embodiment, R³ is a detectable moietybonded to L³ through an S of the detectable moiety. In embodiment, R³ isa detectable moiety bonded to L³ through an O of a —OC(O)— of thedetectable moiety. In embodiment, R³ is a drug moiety. In embodiment, R³is a drug moiety bonded to L³ through an N of the drug moiety. Inembodiment, R³ is a drug moiety bonded to L³ through an O of the drugmoiety. In embodiment, R³ is a drug moiety bonded to L³ through an S ofthe drug moiety. In embodiment, R³ is a drug moiety bonded to L³ throughan O of a —OC(O)— of the drug moiety. In embodiments, L³ is asubstituted or unsubstituted C₁-C₂₀ alkylene. In embodiments, L³ is asubstituted or unsubstituted 2 to 20 membered heteroalkylene. Inembodiments, L³ is a substituted or unsubstituted C₃-C₂₀ cycloalkylene.In embodiments, L³ is a substituted or unsubstituted 3 to 20 memberedheterocycloalkylene. In embodiments, L³ is a substituted orunsubstituted C₆-C₂₀ arylene. In embodiments, L³ is a substituted orunsubstituted 5 to 20 membered heteroarylene. In embodiments, L³ is asubstituted C₁-C₂₀ alkylene. In embodiments, L³ is a substituted 2 to 20membered heteroalkylene. In embodiments, L³ is a substituted C₃-C₂₀cycloalkylene. In embodiments, L³ is a substituted 3 to 20 memberedheterocycloalkylene. In embodiments, L³ is a substituted C₆-C₂₀ arylene.In embodiments, L³ is a substituted 5 to 20 membered heteroarylene. Inembodiments, L³ is an unsubstituted C₁-C₂₀ alkylene. In embodiments, L³is an unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L³is an unsubstituted C₃-C₂₀ cycloalkylene. In embodiments, L³ is anunsubstituted 3 to 20 membered heterocycloalkylene. In embodiments, L³is an unsubstituted C₆-C₂₀ arylene. In embodiments, L³ is anunsubstituted 5 to 20 membered heteroarylene. In embodiments, L³ is asubstituted or unsubstituted C₁-C₁₄ alkylene. In embodiments, L³ is asubstituted or unsubstituted 2 to 14 membered heteroalkylene. Inembodiments, L³ is a substituted or unsubstituted C₃-C₁₄ cycloalkylene.In embodiments, L³ is a substituted or unsubstituted 3 to 14 memberedheterocycloalkylene. In embodiments, L³ is a substituted orunsubstituted C₆-C₁₄ arylene. In embodiments, L³ is a substituted orunsubstituted 5 to 14 membered heteroarylene. In embodiments, L³ is asubstituted C₁-C₁₄ alkylene. In embodiments, L³ is a substituted 2 to 14membered heteroalkylene. In embodiments, L³ is a substituted C₃-C₁₄cycloalkylene. In embodiments, L³ is a substituted 3 to 14 memberedheterocycloalkylene. In embodiments, L³ is a substituted C₆-C₁₄ arylene.In embodiments, L³ is a substituted 5 to 14 membered heteroarylene. Inembodiments, L³ is an unsubstituted C₁-C₁₄ alkylene. In embodiments, L³is an unsubstituted 2 to 14 membered heteroalkylene. In embodiments, L³is an unsubstituted C₃-C₁₄ cycloalkylene. In embodiments, L³ is anunsubstituted 3 to 14 membered heterocycloalkylene. In embodiments, L³is an unsubstituted C₆-C₁₄ arylene. In embodiments, L³ is anunsubstituted 5 to 14 membered heteroarylene. In embodiments, L³ is asubstituted or unsubstituted C₁-C₈ alkylene. In embodiments, L³ is asubstituted or unsubstituted 2 to 8 membered heteroalkylene. Inembodiments, L³ is a substituted or unsubstituted C₃-C₈ cycloalkylene.In embodiments, L³ is a substituted or unsubstituted 3 to 8 memberedheterocycloalkylene. In embodiments, L³ is a substituted orunsubstituted C₆-C₁₀ arylene. In embodiments, L³ is a substituted orunsubstituted 5 to 10 membered heteroarylene. In embodiments, L³ is asubstituted C₁-C₈ alkylene. In embodiments, L³ is a substituted 2 to 8membered heteroalkylene. In embodiments, L³ is a substituted C₃-C₈cycloalkylene. In embodiments, L³ is a substituted 3 to 8 memberedheterocycloalkylene. In embodiments, L³ is a substituted C₆-C₁₀ arylene.In embodiments, L³ is a substituted 5 to 10 membered heteroarylene. Inembodiments, L³ is an unsubstituted C₁-C₈ alkylene. In embodiments, L³is an unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L³is an unsubstituted C₃-C₈ cycloalkylene. In embodiments, L³ is anunsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, L³ isan unsubstituted C₆-C₁₀ arylene. In embodiments, L³ is an unsubstituted5 to 10 membered heteroarylene.

In embodiments L⁴ is a bond. In embodiments L⁴ is —OC(O)—. Inembodiments L⁴ is —OC(O)NH-Ph-CH₂—. In embodiments L⁴ is—OC(O)NH-Ph-CH₂—OC(O)—. In embodiments L⁴ is —NH-Ph-CH₂—. In embodimentsL⁴ is —NH-Ph-CH₂—OC(O)—. In embodiments L⁴ is —O-Ph-CH₂—. In embodimentsL⁴ is —O-Ph-CH₂—OC(O)—. In embodiment, R⁴ is a protein moiety. Inembodiment, R⁴ is a protein moiety bonded to L⁴ through an N of theprotein moiety. In embodiment, R⁴ is a protein moiety bonded to L⁴through an O of the protein moiety. In embodiment, R⁴ is a proteinmoiety bonded to L⁴ through an S of the protein moiety. In embodiment,R⁴ is a protein moiety bonded to L⁴ through an O of a —OC(O)— of theprotein moiety. In embodiment, R⁴ is a detectable moiety. In embodiment,R⁴ is a detectable moiety bonded to L⁴ through an N of the detectablemoiety. In embodiment, R⁴ is a detectable moiety bonded to L⁴ through anO of the detectable moiety. In embodiment, R⁴ is a detectable moietybonded to L⁴ through an S of the detectable moiety. In embodiment, R⁴ isa detectable moiety bonded to L⁴ through an O of a —OC(O)— of thedetectable moiety. In embodiment, R⁴ is a drug moiety. In embodiment, R⁴is a drug moiety bonded to L⁴ through an N of the drug moiety. Inembodiment, R⁴ is a drug moiety bonded to L⁴ through an O of the drugmoiety. In embodiment, R⁴ is a drug moiety bonded to L⁴ through an S ofthe drug moiety. In embodiment, R⁴ is a drug moiety bonded to L⁴ throughan O of a —OC(O)— of the drug moiety.

In embodiments L⁵ is a bond. In embodiments L⁵ is —OC(O)—. Inembodiments L⁵ is —OC(O)NH-Ph-CH₂—. In embodiments L⁵ is—OC(O)NH-Ph-CH₂—OC(O)—. In embodiments L⁵ is —NH-Ph-CH₂—. In embodimentsL⁵ is —NH-Ph-CH₂—OC(O)—. In embodiments L⁵ is —O-Ph-CH₂—. In embodimentsL⁵ is —O-Ph-CH₂—OC(O)—. In embodiment, R⁵ is a protein moiety. Inembodiment, R⁵ is a protein moiety bonded to L⁵ through an N of theprotein moiety. In embodiment, R⁵ is a protein moiety bonded to L⁵through an O of the protein moiety. In embodiment, R⁵ is a proteinmoiety bonded to L⁵ through an S of the protein moiety. In embodiment,R⁵ is a protein moiety bonded to L⁵ through an O of a —OC(O)— of theprotein moiety. In embodiment, R⁵ is a detectable moiety. In embodiment,R⁵ is a detectable moiety bonded to L⁵ through an N of the detectablemoiety. In embodiment, R⁵ is a detectable moiety bonded to L⁵ through anO of the detectable moiety. In embodiment, R⁵ is a detectable moietybonded to L⁵ through an S of the detectable moiety. In embodiment, R⁵ isa detectable moiety bonded to L⁵ through an O of a —OC(O)— of thedetectable moiety. In embodiment, R⁵ is a drug moiety. In embodiment, R⁵is a drug moiety bonded to L⁵ through an N of the drug moiety. Inembodiment, R⁵ is a drug moiety bonded to L⁵ through an O of the drugmoiety. In embodiment, R⁵ is a drug moiety bonded to L⁵ through an S ofthe drug moiety. In embodiment, R⁵ is a drug moiety bonded to L⁵ throughan O of a —OC(O)— of the drug moiety. In embodiments, R⁵ is

In embodiments, R⁵ is

In embodiments, R⁵ is

In embodiments, R⁵ is

X is halide (e.g., Cl or Br). In embodiments, R⁵ is

In embodiments, L⁵ is a substituted or unsubstituted C₁-C₂₀ alkylene. Inembodiments, L⁵ is a substituted or unsubstituted 2 to 20 memberedheteroalkylene. In embodiments, L⁵ is a substituted or unsubstitutedC₃-C₂₀ cycloalkylene. In embodiments, L⁵ is a substituted orunsubstituted 3 to 20 membered heterocycloalkylene. In embodiments, L⁵is a substituted or unsubstituted C₆-C₂₀ arylene. In embodiments, L⁵ isa substituted or unsubstituted 5 to 20 membered heteroarylene. Inembodiments, L⁵ is a substituted C₁-C₂₀ alkylene. In embodiments, L⁵ isa substituted 2 to 20 membered heteroalkylene. In embodiments, L⁵ is asubstituted C₃-C₂₀ cycloalkylene. In embodiments, L⁵ is a substituted 3to 20 membered heterocycloalkylene. In embodiments, L⁵ is a substitutedC₆-C₂₀ arylene. In embodiments, L⁵ is a substituted 5 to 20 memberedheteroarylene. In embodiments, L⁵ is an unsubstituted C₁-C₂₀ alkylene.In embodiments, L⁵ is an unsubstituted 2 to 20 membered heteroalkylene.In embodiments, L⁵ is an unsubstituted C₃-C₂₀ cycloalkylene. Inembodiments, L⁵ is an unsubstituted 3 to 20 memberedheterocycloalkylene. In embodiments, L⁵ is an unsubstituted C₆-C₂₀arylene. In embodiments, L⁵ is an unsubstituted 5 to 20 memberedheteroarylene. In embodiments, L⁵ is a substituted or unsubstitutedC₁-C₁₄ alkylene. In embodiments, L⁵ is a substituted or unsubstituted 2to 14 membered heteroalkylene. In embodiments, L⁵ is a substituted orunsubstituted C₃-C₁₄ cycloalkylene. In embodiments, L⁵ is a substitutedor unsubstituted 3 to 14 membered heterocycloalkylene. In embodiments,L⁵ is a substituted or unsubstituted C₆-C₁₄ arylene. In embodiments, L⁵is a substituted or unsubstituted 5 to 14 membered heteroarylene. Inembodiments, L⁵ is a substituted C₁-C₁₄ alkylene. In embodiments, L⁵ isa substituted 2 to 14 membered heteroalkylene. In embodiments, L⁵ is asubstituted C₃-C₁₄ cycloalkylene. In embodiments, L⁵ is a substituted 3to 14 membered heterocycloalkylene. In embodiments, L⁵ is a substitutedC₆-C₁₄ arylene. In embodiments, L⁵ is a substituted 5 to 14 memberedheteroarylene. In embodiments, L⁵ is an unsubstituted C₁-C₁₄ alkylene.In embodiments, L⁵ is an unsubstituted 2 to 14 membered heteroalkylene.In embodiments, L⁵ is an unsubstituted C₃-C₁₄ cycloalkylene. Inembodiments, L⁵ is an unsubstituted 3 to 14 memberedheterocycloalkylene. In embodiments, L⁵ is an unsubstituted C₆-C₁₄arylene. In embodiments, L⁵ is an unsubstituted 5 to 14 memberedheteroarylene. In embodiments, L⁵ is a substituted or unsubstitutedC₁-C₈ alkylene. In embodiments, L⁵ is a substituted or unsubstituted 2to 8 membered heteroalkylene. In embodiments, L⁵ is a substituted orunsubstituted C₃-C₈ cycloalkylene. In embodiments, L⁵ is a substitutedor unsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, L⁵is a substituted or unsubstituted C₆-C₁₀ arylene. In embodiments, L⁵ isa substituted or unsubstituted 5 to 10 membered heteroarylene. Inembodiments, L⁵ is a substituted C₁-C₈ alkylene. In embodiments, L⁵ is asubstituted 2 to 8 membered heteroalkylene. In embodiments, L⁵ is asubstituted C₃-C₈ cycloalkylene. In embodiments, L⁵ is a substituted 3to 8 membered heterocycloalkylene. In embodiments, L⁵ is a substitutedC₆-C₁₀ arylene. In embodiments, L⁵ is a substituted 5 to 10 memberedheteroarylene. In embodiments, L⁵ is an unsubstituted C₁-C₈ alkylene. Inembodiments, L⁵ is an unsubstituted 2 to 8 membered heteroalkylene. Inembodiments, L⁵ is an unsubstituted C₃-C₈ cycloalkylene. In embodiments,L⁵ is an unsubstituted 3 to 8 membered heterocycloalkylene. Inembodiments, L⁵ is an unsubstituted C₆-C₁₀ arylene. In embodiments, L⁵is an unsubstituted 5 to 10 membered heteroarylene.

In embodiments L⁶ is a bond. In embodiments L⁶ is —OC(O)—. Inembodiments L⁶ is —OC(O)NH-Ph-CH₂—. In embodiments L⁶ is—OC(O)NH-Ph-CH₂—OC(O)—. In embodiments L⁶ is —NH-Ph-CH₂—. In embodimentsL⁶ is —NH-Ph-CH₂—OC(O)—. In embodiments L⁶ is —O-Ph-CH₂—. In embodimentsL⁶ is —O-Ph-CH₂—OC(O)—. In embodiment, R⁶ is a protein moiety. Inembodiment, R⁶ is a protein moiety bonded to L⁶ through an N of theprotein moiety. In embodiment, R⁶ is a protein moiety bonded to L⁶through an O of the protein moiety. In embodiment, R⁶ is a proteinmoiety bonded to L⁶ through an S of the protein moiety. In embodiment,R⁶ is a protein moiety bonded to L⁶ through an O of a —OC(O)— of theprotein moiety. In embodiment, R⁶ is a detectable moiety. In embodiment,R⁶ is a detectable moiety bonded to L⁶ through an N of the detectablemoiety. In embodiment, R⁶ is a detectable moiety bonded to L⁶ through anO of the detectable moiety. In embodiment, R⁶ is a detectable moietybonded to L⁶ through an S of the detectable moiety. In embodiment, R⁶ isa detectable moiety bonded to L⁶ through an O of a —OC(O)— of thedetectable moiety. In embodiment, R⁶ is a drug moiety. In embodiment, R⁶is a drug moiety bonded to L⁶ through an N of the drug moiety. Inembodiment, R⁶ is a drug moiety bonded to L⁶ through an O of the drugmoiety. In embodiment, R⁶ is a drug moiety bonded to L⁶ through an S ofthe drug moiety. In embodiment, R⁶ is a drug moiety bonded to L⁶ throughan O of a —OC(O)— of the drug moiety.

In embodiments L⁷ is a bond. In embodiments L⁷ is —OC(O)—. Inembodiments L⁷ is —OC(O)NH-Ph-CH₂—. In embodiments L⁷ is—OC(O)NH-Ph-CH₂—OC(O)—. In embodiments L⁷ is —NH-Ph-CH₂—. In embodimentsL⁷ is —NH-Ph-CH₂—OC(O)—. In embodiments L⁷ is —O-Ph-CH₂—. In embodimentsL⁷ is —O-Ph-CH₂—OC(O)—. In embodiment, R⁷ is a protein moiety. Inembodiment, R⁷ is a protein moiety bonded to L⁷ through an N of theprotein moiety. In embodiment, R⁷ is a protein moiety bonded to L⁷through an O of the protein moiety. In embodiment, R⁷ is a proteinmoiety bonded to L⁷ through an S of the protein moiety. In embodiment,R⁷ is a protein moiety bonded to L⁷ through an O of a —OC(O)— of theprotein moiety. In embodiment, R⁷ is a detectable moiety. In embodiment,R⁷ is a detectable moiety bonded to L⁷ through an N of the detectablemoiety. In embodiment, R⁷ is a detectable moiety bonded to L⁷ through anO of the detectable moiety. In embodiment, R⁷ is a detectable moietybonded to L⁷ through an S of the detectable moiety. In embodiment, R⁷ isa detectable moiety bonded to L⁷ through an O of a —OC(O)— of thedetectable moiety. In embodiment, R⁷ is a drug moiety. In embodiment, R⁷is a drug moiety bonded to L⁷ through an N of the drug moiety. Inembodiment, R⁷ is a drug moiety bonded to L⁷ through an O of the drugmoiety. In embodiment, R⁷ is a drug moiety bonded to L⁷ through an S ofthe drug moiety. In embodiment, R⁷ is a drug moiety bonded to L⁷ throughan O of a —OC(O)— of the drug moiety. In embodiments, R⁷ is

In embodiments, R⁷ is

In embodiments, R⁷ is

In embodiments, R⁷ is

X is halide (e.g., Cl or Br). In embodiments, R⁷ is

In embodiments, L⁷ is a substituted or unsubstituted C₁-C₂₀ alkylene. Inembodiments, L⁷ is a substituted or unsubstituted 2 to 20 memberedheteroalkylene. In embodiments, L⁷ is a substituted or unsubstitutedC₃-C₂₀ cycloalkylene. In embodiments, L⁷ is a substituted orunsubstituted 3 to 20 membered heterocycloalkylene. In embodiments, L⁷is a substituted or unsubstituted C₆-C₂₀ arylene. In embodiments, L⁷ isa substituted or unsubstituted 5 to 20 membered heteroarylene. Inembodiments, L⁷ is a substituted C₁-C₂₀ alkylene. In embodiments, L⁷ isa substituted 2 to 20 membered heteroalkylene. In embodiments, L⁷ is asubstituted C₃-C₂₀ cycloalkylene. In embodiments, L⁷ is a substituted 3to 20 membered heterocycloalkylene. In embodiments, L⁷ is a substitutedC₆-C₂₀ arylene. In embodiments, L⁷ is a substituted 5 to 20 memberedheteroarylene. In embodiments, L⁷ is an unsubstituted C₁-C₂₀ alkylene.In embodiments, L⁷ is an unsubstituted 2 to 20 membered heteroalkylene.In embodiments, L⁷ is an unsubstituted C₃-C₂₀ cycloalkylene. Inembodiments, L⁷ is an unsubstituted 3 to 20 memberedheterocycloalkylene. In embodiments, L⁷ is an unsubstituted C₆-C₂₀arylene. In embodiments, L⁷ is an unsubstituted 5 to 20 memberedheteroarylene. In embodiments, L⁷ is a substituted or unsubstitutedC₁-C₁₄ alkylene. In embodiments, L⁷ is a substituted or unsubstituted 2to 14 membered heteroalkylene. In embodiments, L⁷ is a substituted orunsubstituted C₃-C₁₄ cycloalkylene. In embodiments, L⁷ is a substitutedor unsubstituted 3 to 14 membered heterocycloalkylene. In embodiments,L⁷ is a substituted or unsubstituted C₆-C₁₄ arylene. In embodiments, L⁷is a substituted or unsubstituted 5 to 14 membered heteroarylene. Inembodiments, L⁷ is a substituted C₁-C₁₄ alkylene. In embodiments, L⁷ isa substituted 2 to 14 membered heteroalkylene. In embodiments, L⁷ is asubstituted C₃-C₁₄ cycloalkylene. In embodiments, L⁷ is a substituted 3to 14 membered heterocycloalkylene. In embodiments, L⁷ is a substitutedC₆-C₁₄ arylene. In embodiments, L⁷ is a substituted 5 to 14 memberedheteroarylene. In embodiments, L⁷ is an unsubstituted C₁-C₁₄ alkylene.In embodiments, L⁷ is an unsubstituted 2 to 14 membered heteroalkylene.In embodiments, L⁷ is an unsubstituted C₃-C₁₄ cycloalkylene. Inembodiments, L⁷ is an unsubstituted 3 to 14 memberedheterocycloalkylene. In embodiments, L⁷ is an unsubstituted C₆-C₁₄arylene. In embodiments, L⁷ is an unsubstituted 5 to 14 memberedheteroarylene. In embodiments, L⁷ is a substituted or unsubstitutedC₁-C₈ alkylene. In embodiments, L⁷ is a substituted or unsubstituted 2to 8 membered heteroalkylene. In embodiments, L⁷ is a substituted orunsubstituted C₃-C₈ cycloalkylene. In embodiments, L⁷ is a substitutedor unsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, L⁷is a substituted or unsubstituted C₆-C₁₀ arylene. In embodiments, L⁷ isa substituted or unsubstituted 5 to 10 membered heteroarylene. Inembodiments, L⁷ is a substituted C₁-C₈ alkylene. In embodiments, L⁷ is asubstituted 2 to 8 membered heteroalkylene. In embodiments, L⁷ is asubstituted C₃-C₈ cycloalkylene. In embodiments, L⁷ is a substituted 3to 8 membered heterocycloalkylene. In embodiments, L⁷ is a substitutedC₆-C₁₀ arylene. In embodiments, L⁷ is a substituted 5 to 10 memberedheteroarylene. In embodiments, L⁷ is an unsubstituted C₁-C₈ alkylene. Inembodiments, L⁷ is an unsubstituted 2 to 8 membered heteroalkylene. Inembodiments, L⁷ is an unsubstituted C₃-C₈ cycloalkylene. In embodiments,L⁷ is an unsubstituted 3 to 8 membered heterocycloalkylene. Inembodiments, L⁷ is an unsubstituted C₆-C₁₀ arylene. In embodiments, L⁷is an unsubstituted 5 to 10 membered heteroarylene.

In embodiments L⁸ is a bond. In embodiments L⁸ is —OC(O)—. Inembodiments L⁸ is —OC(O)NH-Ph-CH₂—. In embodiments L⁸ is—OC(O)NH-Ph-CH₂—OC(O)—. In embodiments L⁸ is —NH-Ph-CH₂—. In embodimentsL⁸ is —NH-Ph-CH₂—OC(O)—. In embodiments L⁸ is —O-Ph-CH₂—. In embodimentsL⁸ is —O-Ph-CH₂—OC(O)—. In embodiment, R⁸ is a protein moiety. Inembodiment, R⁸ is a protein moiety bonded to L⁸ through an N of theprotein moiety. In embodiment, R⁸ is a protein moiety bonded to L⁸through an O of the protein moiety. In embodiment, R⁸ is a proteinmoiety bonded to L⁸ through an S of the protein moiety. In embodiment,R⁸ is a protein moiety bonded to L⁸ through an O of a —OC(O)— of theprotein moiety. In embodiment, R⁸ is a detectable moiety. In embodiment,R⁸ is a detectable moiety bonded to L⁸ through an N of the detectablemoiety. In embodiment, R⁸ is a detectable moiety bonded to L⁸ through anO of the detectable moiety. In embodiment, R⁸ is a detectable moietybonded to L⁸ through an S of the detectable moiety. In embodiment, R⁸ isa detectable moiety bonded to L⁸ through an O of a —OC(O)— of thedetectable moiety. In embodiment, R⁸ is a drug moiety. In embodiment, R⁸is a drug moiety bonded to L⁸ through an N of the drug moiety. Inembodiment, R⁸ is a drug moiety bonded to L⁸ through an O of the drugmoiety. In embodiment, R⁸ is a drug moiety bonded to L⁸ through an S ofthe drug moiety. In embodiment, R⁸ is a drug moiety bonded to L⁸ throughan O of a —OC(O)— of the drug moiety.

In embodiments L⁹ is a bond. In embodiments L⁹ is —OC(O)—. Inembodiments L⁹ is —OC(O)NH-Ph-CH₂—. In embodiments L⁹ is—OC(O)NH-Ph-CH₂—OC(O)—. In embodiments L⁹ is —NH-Ph-CH₂—. In embodimentsL⁹ is —NH-Ph-CH₂—OC(O)—. In embodiments L⁹ is —O-Ph-CH₂—. In embodimentsL⁹ is —O-Ph-CH₂—OC(O)—. In embodiment, R⁹ is a protein moiety. Inembodiment, R⁹ is a protein moiety bonded to L⁹ through an N of theprotein moiety. In embodiment, R⁹ is a protein moiety bonded to L⁹through an O of the protein moiety. In embodiment, R⁹ is a proteinmoiety bonded to L⁹ through an S of the protein moiety. In embodiment,R⁹ is a protein moiety bonded to L⁹ through an O of a —OC(O)— of theprotein moiety. In embodiment, R⁹ is a detectable moiety. In embodiment,R⁹ is a detectable moiety bonded to L⁹ through an N of the detectablemoiety. In embodiment, R⁹ is a detectable moiety bonded to L⁹ through anO of the detectable moiety. In embodiment, R⁹ is a detectable moietybonded to L⁹ through an S of the detectable moiety. In embodiment, R⁹ isa detectable moiety bonded to L⁹ through an O of a —OC(O)— of thedetectable moiety. In embodiment, R⁹ is a drug moiety. In embodiment, R⁹is a drug moiety bonded to L⁹ through an N of the drug moiety. Inembodiment, R⁹ is a drug moiety bonded to L⁹ through an O of the drugmoiety. In embodiment, R⁹ is a drug moiety bonded to L⁹ through an S ofthe drug moiety. In embodiment, R⁹ is a drug moiety bonded to L⁹ throughan O of a —OC(O)— of the drug moiety. In embodiments, L⁹ is asubstituted or unsubstituted C₁-C₂₀ alkylene. In embodiments, L⁹ is asubstituted or unsubstituted 2 to 20 membered heteroalkylene. Inembodiments, L⁹ is a substituted or unsubstituted C₃-C₂₀ cycloalkylene.In embodiments, L⁹ is a substituted or unsubstituted 3 to 20 memberedheterocycloalkylene. In embodiments, L⁹ is a substituted orunsubstituted C₆-C₂₀ arylene. In embodiments, L⁹ is a substituted orunsubstituted 5 to 20 membered heteroarylene. In embodiments, L⁹ is asubstituted C₁-C₂₀ alkylene. In embodiments, L⁹ is a substituted 2 to 20membered heteroalkylene. In embodiments, L⁹ is a substituted C₃-C₂₀cycloalkylene. In embodiments, L⁹ is a substituted 3 to 20 memberedheterocycloalkylene. In embodiments, L⁹ is a substituted C₆-C₂₀ arylene.In embodiments, L⁹ is a substituted 5 to 20 membered heteroarylene. Inembodiments, L⁹ is an unsubstituted C₁-C₂₀ alkylene. In embodiments, L⁹is an unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L⁹is an unsubstituted C₃-C₂₀ cycloalkylene. In embodiments, L⁹ is anunsubstituted 3 to 20 membered heterocycloalkylene. In embodiments, L⁹is an unsubstituted C₆-C₂₀ arylene. In embodiments, L⁹ is anunsubstituted 5 to 20 membered heteroarylene. In embodiments, L⁹ is asubstituted or unsubstituted C₁-C₁₄ alkylene. In embodiments, L⁹ is asubstituted or unsubstituted 2 to 14 membered heteroalkylene. Inembodiments, L⁹ is a substituted or unsubstituted C₃-C₁₄ cycloalkylene.In embodiments, L⁹ is a substituted or unsubstituted 3 to 14 memberedheterocycloalkylene. In embodiments, L⁹ is a substituted orunsubstituted C₆-C₁₄ arylene. In embodiments, L⁹ is a substituted orunsubstituted 5 to 14 membered heteroarylene. In embodiments, L⁹ is asubstituted C₁-C₁₄ alkylene. In embodiments, L⁹ is a substituted 2 to 14membered heteroalkylene. In embodiments, L⁹ is a substituted C₃-C₁₄cycloalkylene. In embodiments, L⁹ is a substituted 3 to 14 memberedheterocycloalkylene. In embodiments, L⁹ is a substituted C₆-C₁₄ arylene.In embodiments, L⁹ is a substituted 5 to 14 membered heteroarylene. Inembodiments, L⁹ is an unsubstituted C₁-C₁₄ alkylene. In embodiments, L⁹is an unsubstituted 2 to 14 membered heteroalkylene. In embodiments, L⁹is an unsubstituted C₃-C₁₄ cycloalkylene. In embodiments, L⁹ is anunsubstituted 3 to 14 membered heterocycloalkylene. In embodiments, L⁹is an unsubstituted C₆-C₁₄ arylene. In embodiments, L⁹ is anunsubstituted 5 to 14 membered heteroarylene. In embodiments, L⁹ is asubstituted or unsubstituted C₁-C₈ alkylene. In embodiments, L⁹ is asubstituted or unsubstituted 2 to 8 membered heteroalkylene. Inembodiments, L⁹ is a substituted or unsubstituted C₃-C₈ cycloalkylene.In embodiments, L⁹ is a substituted or unsubstituted 3 to 8 memberedheterocycloalkylene. In embodiments, L⁹ is a substituted orunsubstituted C₆-C₁₀ arylene. In embodiments, L⁹ is a substituted orunsubstituted 5 to 10 membered heteroarylene. In embodiments, L⁹ is asubstituted C₁-C₈ alkylene. In embodiments, L⁹ is a substituted 2 to 8membered heteroalkylene. In embodiments, L⁹ is a substituted C₃-C₈cycloalkylene. In embodiments, L⁹ is a substituted 3 to 8 memberedheterocycloalkylene. In embodiments, L⁹ is a substituted C₆-C₁₀ arylene.In embodiments, L⁹ is a substituted 5 to 10 membered heteroarylene. Inembodiments, L⁹ is an unsubstituted C₁-C₈ alkylene. In embodiments, L⁹is an unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L⁹is an unsubstituted C₃-C₈ cycloalkylene. In embodiments, L⁹ is anunsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, L⁹ isan unsubstituted C₆-C₁₀ arylene. In embodiments, L⁹ is an unsubstituted5 to 10 membered heteroarylene.

In embodiments L¹¹ is a bond. In embodiments L¹¹ is —OC(O)—. Inembodiments L¹¹ is —OC(O)NH-Ph-CH₂—. In embodiments L¹¹ is—OC(O)NH-Ph-CH₂—OC(O)—. In embodiments L¹¹ is —NH-Ph-CH₂—. Inembodiments L¹¹ is —NH-Ph-CH₂—OC(O)—. In embodiments L¹¹ is —O-Ph-CH₂—.In embodiments L¹¹ is —O-Ph-CH₂—OC(O)—. In embodiment, R¹¹ is a proteinmoiety. In embodiment, R¹¹ is a protein moiety bonded to L¹¹ through anN of the protein moiety. In embodiment, R¹¹ is a protein moiety bondedto L¹¹ through an O of the protein moiety. In embodiment, R¹¹ is aprotein moiety bonded to L¹¹ through an S of the protein moiety. Inembodiment, R¹¹ is a protein moiety bonded to L¹¹ through an O of a—OC(O)— of the protein moiety. In embodiment, R¹¹ is a detectablemoiety. In embodiment, R¹¹ is a detectable moiety bonded to L¹¹ throughan N of the detectable moiety. In embodiment, R¹¹ is a detectable moietybonded to L¹¹ through an O of the detectable moiety. In embodiment, R¹¹is a detectable moiety bonded to L¹¹ through an S of the detectablemoiety. In embodiment, R¹¹ is a detectable moiety bonded to L¹¹ throughan O of a —OC(O)— of the detectable moiety. In embodiment, R¹¹ is a drugmoiety. In embodiment, R¹¹ is a drug moiety bonded to L¹¹ through an Nof the drug moiety. In embodiment, R¹¹ is a drug moiety bonded to L¹¹through an O of the drug moiety. In embodiment, R¹¹ is a drug moietybonded to L¹¹ through an S of the drug moiety. In embodiment, R¹¹ is adrug moiety bonded to L¹¹ through an O of a —OC(O)— of the drug moiety.In embodiments, R¹¹ is

In embodiments, R¹¹

In embodiments, R¹¹ is

In embodiments, R¹¹ is

X is halide (e.g., Cl or Br). In embodiments, R¹¹ is

In embodiments, L¹ is a substituted or unsubstituted C₁-C₂₀ alkylene. Inembodiments, L¹¹ is a substituted or unsubstituted 2 to 20 memberedheteroalkylene. In embodiments, L¹¹ is a substituted or unsubstitutedC₃-C₂₀ cycloalkylene. In embodiments, L¹¹ is a substituted orunsubstituted 3 to 20 membered heterocycloalkylene. In embodiments, L¹¹is a substituted or unsubstituted C₆-C₂₀ arylene. In embodiments, L¹¹ isa substituted or unsubstituted 5 to 20 membered heteroarylene. Inembodiments, L¹¹ is a substituted C₁-C₂₀ alkylene. In embodiments, L¹¹is a substituted 2 to 20 membered heteroalkylene. In embodiments, L¹¹ isa substituted C₃-C₂₀ cycloalkylene. In embodiments, L¹¹ is a substituted3 to 20 membered heterocycloalkylene. In embodiments, L¹¹ is asubstituted C₆-C₂₀ arylene. In embodiments, L¹¹ is a substituted 5 to 20membered heteroarylene. In embodiments, L¹¹ is an unsubstituted C₁-C₂₀alkylene. In embodiments, L¹¹ is an unsubstituted 2 to 20 memberedheteroalkylene. In embodiments, L¹¹ is an unsubstituted C₃-C₂₀cycloalkylene. In embodiments, L¹¹ is an unsubstituted 3 to 20 memberedheterocycloalkylene. In embodiments, L¹¹ is an unsubstituted C₆-C₂₀arylene. In embodiments, L¹¹ is an unsubstituted 5 to 20 memberedheteroarylene. In embodiments, L¹ is a substituted or unsubstitutedC₁-C₁₄ alkylene. In embodiments, L¹¹ is a substituted or unsubstituted 2to 14 membered heteroalkylene. In embodiments, L¹¹ is a substituted orunsubstituted C₃-C₁₄ cycloalkylene. In embodiments, L¹¹ is a substitutedor unsubstituted 3 to 14 membered heterocycloalkylene. In embodiments,L¹¹ is a substituted or unsubstituted C₆-C₁₄ arylene. In embodiments,L¹¹ is a substituted or unsubstituted 5 to 14 membered heteroarylene. Inembodiments, L¹¹ is a substituted C₁-C₁₄ alkylene. In embodiments, L¹¹is a substituted 2 to 14 membered heteroalkylene. In embodiments, L¹¹ isa substituted C₃-C₁₄ cycloalkylene. In embodiments, L¹¹ is a substituted3 to 14 membered heterocycloalkylene. In embodiments, L¹¹ is asubstituted C₆-C₁₄ arylene. In embodiments, L¹¹ is a substituted 5 to 14membered heteroarylene. In embodiments, L¹¹ is an unsubstituted C₁-C₁₄alkylene. In embodiments, L¹¹ is an unsubstituted 2 to 14 memberedheteroalkylene. In embodiments, L¹¹ is an unsubstituted C₃-C₁₄cycloalkylene. In embodiments, L¹¹ is an unsubstituted 3 to 14 memberedheterocycloalkylene. In embodiments, L¹¹ is an unsubstituted C₆-C₁₄arylene. In embodiments, L¹ is an unsubstituted 5 to 14 memberedheteroarylene. In embodiments, L¹ is a substituted or unsubstitutedC₁-C₈ alkylene. In embodiments, L¹¹ is a substituted or unsubstituted 2to 8 membered heteroalkylene. In embodiments, L¹¹ is a substituted orunsubstituted C₃-C₈ cycloalkylene. In embodiments, L¹¹ is a substitutedor unsubstituted 3 to 8 membered heterocycloalkylene. In embodiments,L¹¹ is a substituted or unsubstituted C₆-C₁₀ arylene. In embodiments,L¹¹ is a substituted or unsubstituted 5 to 10 membered heteroarylene. Inembodiments, L¹¹ is a substituted C₁-C₈ alkylene. In embodiments, L¹¹ isa substituted 2 to 8 membered heteroalkylene. In embodiments, L¹¹ is asubstituted C₃-C₈ cycloalkylene. In embodiments, L¹¹ is a substituted 3to 8 membered heterocycloalkylene. In embodiments, L¹¹ is a substitutedC₆-C₁₀ arylene. In embodiments, L¹¹ is a substituted 5 to 10 memberedheteroarylene. In embodiments, L¹¹ is an unsubstituted C₁-C₈ alkylene.In embodiments, L¹¹ is an unsubstituted 2 to 8 membered heteroalkylene.In embodiments, L¹¹ is an unsubstituted C₃-C₈ cycloalkylene. Inembodiments, L¹¹ is an unsubstituted 3 to 8 memberedheterocycloalkylene. In embodiments, L¹¹ is an unsubstituted C₆-C₁₀arylene. In embodiments, L¹¹ is an unsubstituted 5 to 10 memberedheteroarylene.

In embodiments L¹² is a bond. In embodiments L¹² is —OC(O)—. Inembodiments L¹² is —OC(O)NH-Ph-CH₂—. In embodiments L¹² is—OC(O)NH-Ph-CH₂—OC(O)—. In embodiments L¹² is —NH-Ph-CH₂—. Inembodiments L¹² is —NH-Ph-CH₂—OC(O)—. In embodiments L¹² is —O-Ph-CH₂—.In embodiments L¹² is —O-Ph-CH₂—OC(O)—. In embodiment, R¹² is a proteinmoiety. In embodiment, R¹² is a protein moiety bonded to L¹² through anN of the protein moiety. In embodiment, R¹² is a protein moiety bondedto L¹² through an O of the protein moiety. In embodiment, R¹² is aprotein moiety bonded to L¹² through an S of the protein moiety. Inembodiment, R¹² is a protein moiety bonded to L¹² through an O of a—OC(O)— of the protein moiety. In embodiment, R¹² is a detectablemoiety. In embodiment, R¹² is a detectable moiety bonded to L¹² throughan N of the detectable moiety. In embodiment, R¹² is a detectable moietybonded to L¹² through an O of the detectable moiety. In embodiment, R¹²is a detectable moiety bonded to L¹² through an S of the detectablemoiety. In embodiment, R¹² is a detectable moiety bonded to L¹² throughan O of a —OC(O)— of the detectable moiety. In embodiment, R¹² is a drugmoiety. In embodiment, R¹² is a drug moiety bonded to L¹² through an Nof the drug moiety. In embodiment, R¹² is a drug moiety bonded to L¹²through an O of the drug moiety. In embodiment, R¹² is a drug moietybonded to L¹² through an S of the drug moiety. In embodiment, R¹² is adrug moiety bonded to L¹² through an O of a —OC(O)— of the drug moiety.In embodiments, L¹² is a substituted or unsubstituted C₁-C₂₀ alkylene.In embodiments, L¹² is a substituted or unsubstituted 2 to 20 memberedheteroalkylene. In embodiments, L¹² is a substituted or unsubstitutedC₃-C₂₀ cycloalkylene. In embodiments, L¹² is a substituted orunsubstituted 3 to 20 membered heterocycloalkylene. In embodiments, L¹²is a substituted or unsubstituted C₆-C₂₀ arylene. In embodiments, L¹² isa substituted or unsubstituted 5 to 20 membered heteroarylene. Inembodiments, L¹² is a substituted C₁-C₂₀ alkylene. In embodiments, L¹²is a substituted 2 to 20 membered heteroalkylene. In embodiments, L¹² isa substituted C₃-C₂₀ cycloalkylene. In embodiments, L¹² is a substituted3 to 20 membered heterocycloalkylene. In embodiments, L¹² is asubstituted C₆-C₂₀ arylene. In embodiments, L¹² is a substituted 5 to 20membered heteroarylene. In embodiments, L¹² is an unsubstituted C₁-C₂₀alkylene. In embodiments, L¹² is an unsubstituted 2 to 20 memberedheteroalkylene. In embodiments, L¹² is an unsubstituted C₃-C₂₀cycloalkylene. In embodiments, L¹² is an unsubstituted 3 to 20 memberedheterocycloalkylene. In embodiments, L¹² is an unsubstituted C₆-C₂₀arylene. In embodiments, L¹² is an unsubstituted 5 to 20 memberedheteroarylene. In embodiments, L¹² is a substituted or unsubstitutedC₁-C₁₄ alkylene. In embodiments, L¹² is a substituted or unsubstituted 2to 14 membered heteroalkylene. In embodiments, L¹² is a substituted orunsubstituted C₃-C₁₄ cycloalkylene. In embodiments, L¹² is a substitutedor unsubstituted 3 to 14 membered heterocycloalkylene. In embodiments,L¹² is a substituted or unsubstituted C₆-C₁₄ arylene. In embodiments,L¹² is a substituted or unsubstituted 5 to 14 membered heteroarylene. Inembodiments, L¹² is a substituted C₁-C₁₄ alkylene. In embodiments, L¹²is a substituted 2 to 14 membered heteroalkylene. In embodiments, L¹² isa substituted C₃-C₁₄ cycloalkylene. In embodiments, L¹² is a substituted3 to 14 membered heterocycloalkylene. In embodiments, L¹² is asubstituted C₆-C₁₄ arylene. In embodiments, L¹² is a substituted 5 to 14membered heteroarylene. In embodiments, L¹² is an unsubstituted C₁-C₁₄alkylene. In embodiments, L¹² is an unsubstituted 2 to 14 memberedheteroalkylene. In embodiments, L¹² is an unsubstituted C₃-C₁₄cycloalkylene. In embodiments, L¹² is an unsubstituted 3 to 14 memberedheterocycloalkylene. In embodiments, L¹² is an unsubstituted C₆-C₁₄arylene. In embodiments, L¹² is an unsubstituted 5 to 14 memberedheteroarylene. In embodiments, L¹² is a substituted or unsubstitutedC₁-C₈ alkylene. In embodiments, L¹² is a substituted or unsubstituted 2to 8 membered heteroalkylene. In embodiments, L¹² is a substituted orunsubstituted C₃-C₈ cycloalkylene. In embodiments, L¹² is a substitutedor unsubstituted 3 to 8 membered heterocycloalkylene. In embodiments,L¹² is a substituted or unsubstituted C₆-C₁₀ arylene. In embodiments,L¹² is a substituted or unsubstituted 5 to 10 membered heteroarylene. Inembodiments, L¹² is a substituted C₁-C₈ alkylene. In embodiments, L¹² isa substituted 2 to 8 membered heteroalkylene. In embodiments, L¹² is asubstituted C₃-C₈ cycloalkylene. In embodiments, L¹² is a substituted 3to 8 membered heterocycloalkylene. In embodiments, L¹² is a substitutedC₆-C₁₀ arylene. In embodiments, L¹² is a substituted 5 to 10 memberedheteroarylene. In embodiments, L¹² is an unsubstituted C₁-C₈ alkylene.In embodiments, L¹² is an unsubstituted 2 to 8 membered heteroalkylene.In embodiments, L¹² is an unsubstituted C₃-C₈ cycloalkylene. Inembodiments, L¹² is an unsubstituted 3 to 8 memberedheterocycloalkylene. In embodiments, L¹² is an unsubstituted C₆-C₁₀arylene. In embodiments, L¹² is an unsubstituted 5 to 10 memberedheteroarylene.

As described above, each L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, L⁹, L¹¹, and L¹²may be different. Where each of L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, L⁹, L¹¹, andL¹² are different, L¹³ may be referred to as L¹³², L¹³³, L¹³⁴, L¹³⁵,L¹³⁶, L¹³⁷, L¹³⁸, L¹³⁹, L¹³¹¹, and L¹³¹² to refer to L¹³ substituentsthat correlate to L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, L⁹, L¹¹, and L¹²,respectively. Likewise, where each of L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, L⁹,L¹¹, and L¹² are different, L¹⁴ may be referred to as L¹⁴², L¹⁴³, L¹⁴⁴,L¹⁴⁵, L¹⁴⁶, L¹⁴⁷, L¹⁴⁸, L¹⁴⁹, L¹⁴¹¹, and L¹⁴¹² to refer to L¹⁴substituents that correlate to L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, L⁹, L¹¹, andL¹², respectively. Likewise, where each of L², L³, L⁴, L⁵, L⁶, L⁷, L⁸,L⁹, L¹¹, and L¹² are different, R¹⁷ may be referred to as R¹⁷², R¹⁷³,R¹⁷⁴, R¹⁷⁵, R¹⁷⁶, R¹⁷⁷, R¹⁷⁸, R¹⁷⁹, R¹⁷¹¹, and R¹⁷¹² to refer to R¹⁷substituents that correlate to L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, L⁹, L¹¹, andL¹², respectively. For example, in embodiments, L² is a bond,—N(R¹⁷²)-L¹³²-L¹⁴²-, —N(R¹⁷²)C(O)O-L¹³²-L¹⁴²-, —O-L¹³²-L¹⁴²-,—S-L¹³²-L¹⁴²-, —OC(O)-L¹³²-L¹⁴²-, —O C(O)N(R¹⁷²)-L¹³²-L¹⁴²-,—OC(O)O-L¹³²-L¹⁴²-, —OSO₂-L¹³²-L¹⁴², —C(O)N(R¹⁷²)-L¹³²-L¹⁴²-,—N(R¹⁷²)C(O)-L¹³²-L¹⁴²-, —S(O)₂N(R¹⁷²)-L¹³²-L¹⁴²-,—N(R¹⁷²)S(O)₂-L¹³²-L¹⁴²-, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene. Likewise, embodiments, L¹²is a bond, —N(R¹⁷¹²)-L¹³¹²-L¹⁴¹²-, —N(R¹⁷¹²)C(O)O-L¹³¹²-L¹⁴¹²-,—O-L¹³¹²-L¹⁴¹²-, —S-L¹³¹²-L¹⁴¹²-, —OC(O)-L¹³¹²-L¹⁴¹²,—OC(O)N(R¹⁷¹²)-L¹³¹²-L¹⁴¹²-, —OC(O)O-L¹³¹²-L¹⁴¹²-, —OSO₂-L¹³¹²-L¹⁴¹²-,—C(O)N(R¹⁷¹²)-L¹³²-L¹⁴¹²-, —N(R¹⁷¹²)C(O)-L¹³¹²-L¹⁴¹²-,—S(O)₂N(R¹⁷¹²)-L¹³²¹-L¹⁴¹²-, —N(R¹⁷¹²)S(O)₂-L¹³¹²-L¹⁴¹²-, substituted orunsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene.

In embodiments, each L¹³ is independently selected from a bond orsubstituted or unsubstituted arylene. In embodiments, each L¹³ isindependently selected from a bond or substituted or unsubstitutedphenylene. In embodiments, each L¹⁴ is independently selected from abond, substituted or unsubstituted alkylene, or substituted orunsubstituted heteroalkylene. In embodiments, each L¹⁴ is independentlyselected from a bond, —(CH₂)_(w)—, or —(CH₂)_(w)—OC(O)—; and w is aninteger between 1 and 4. In embodiments, each -L¹³-L¹⁴- is independentlyselected from a bond, -Ph-(CH₂)_(w)—, or -Ph-(CH₂)_(w)—OC(O)—; and w isan integer between 1 and 4. In embodiments, -L¹³-L¹⁴- is a bond. Inembodiments, -L¹³-L¹⁴- is -Ph-(CH₂)_(w)—. In embodiments, -L¹³-L¹⁴- is-Ph-(CH₂)_(w)—OC(O)—. In embodiments, w is 1. In embodiments, w is 2. Inembodiments, w is 3. In embodiments, w is 4. In embodiments, -L¹³-L¹⁴-is independently -Ph-CH₂—, or -Ph-CH₂—OC(O)—. In embodiments, one ormore linkers (e.g. L¹, L², L³, L⁵, L⁶, L⁷, L⁸, L⁹, L¹¹, and/or L¹²)connected to an R group including a drug moiety, protein moiety, ordetectable moiety is —OC(O)NH-Ph-CH₂—, —OC(O)NH-Ph-CH₂—OC(O)—,—NH-Ph-CH₂—, —NH-Ph-CH₂—OC(O)—, —O-Ph-CH₂—, or —O-Ph-CH₂—OC(O)—(collectively “extended linkers”). In embodiments, L¹³ is independentlya bond. In embodiments, L¹³ is independently an unsubstituted arylene.In embodiments, L¹³ is independently a substituted arylene. Inembodiments, L¹⁴ is independently a bond. In embodiments, L¹⁴ isindependently an unsubstituted methylene. In embodiments, L¹⁴ isindependently an unsubstituted ethylene. In embodiments, L¹⁴ isindependently an unsubstituted propylene. In embodiments, L¹⁴ isindependently an unsubstituted butylene. In embodiments, each L¹⁴ isindependently a —(CH₂)—. In embodiments, each L¹⁴ is independently a—(CH₂)₂—. In embodiments, each L¹⁴ is independently a —(CH₂)₃—. Inembodiments, each L¹⁴ is independently a —(CH₂)₄—. In embodiments, eachL¹⁴ is independently a —(CH₂)—OC(O)—. In embodiments, each L¹⁴ isindependently a —(CH₂)₂—OC(O)—. In embodiments, each L¹⁴ isindependently a —(CH₂)₃—OC(O)—. In embodiments, each L¹⁴ isindependently a —(CH₂)₄—OC(O)—.

In embodiments, L¹³ is —NHC(O)—(CH₂)_(W)—NHC(O)O—(CH₂)_(Y1)—. Inembodiments, L¹³ is —NHC(O)—(CH₂)_(W)—C(O)NH—(CH₂)_(Y1)—. Inembodiments, L¹³ is —NHC(O)—(CH₂)_(W)—C(O)—. In embodiments, L¹³ is—NHC(O)—(CH₂)_(W)—NH—. In embodiments, L¹³ is —NHC(O)—(CH₂)_(W)—NHC(O)—.In embodiments, L¹³ is —NHC(O)—(CH₂)_(W)—C(O)NH—. In embodiments, L¹³ is—NHC(O)—(CH₂)_(W)—NHC(O)O—. In embodiments, L¹³ is—NHC(O)—(CH₂)_(W)—(OCH₂CH₂)_(T1)—C(O)NH—(CH₂)_(Y1)—. In embodiments, L¹³is —NHC(O)—(CH₂)_(W)—(OCH₂CH₂)_(T1)—C(O)NH—(CH₂)_(Y1)—C(O)—. Inembodiments, L¹³ is a substituted or unsubstituted C₁-C₂₀ alkylene. Inembodiments, L¹³ is a substituted or unsubstituted 2 to 20 memberedheteroalkylene. In embodiments, L¹³ is a substituted or unsubstitutedC₃-C₂₀ cycloalkylene. In embodiments, L¹³ is a substituted orunsubstituted 3 to 20 membered heterocycloalkylene. In embodiments, L¹³is a substituted or unsubstituted C₆-C₂₀ arylene. In embodiments, L¹³ isa substituted or unsubstituted 5 to 20 membered heteroarylene. Inembodiments, L¹³ is a substituted C₁-C₂₀ alkylene. In embodiments, L¹³is a substituted 2 to 20 membered heteroalkylene. In embodiments, L¹³ isa substituted C₃-C₂₀ cycloalkylene. In embodiments, L¹³ is a substituted3 to 20 membered heterocycloalkylene. In embodiments, L¹³ is asubstituted C₆-C₂₀ arylene. In embodiments, L¹³ is a substituted 5 to 20membered heteroarylene. In embodiments, L¹³ is an unsubstituted C₁-C₂₀alkylene. In embodiments, L¹³ is an unsubstituted 2 to 20 memberedheteroalkylene. In embodiments, L¹³ is an unsubstituted C₃-C₂₀cycloalkylene. In embodiments, L¹³ is an unsubstituted 3 to 20 memberedheterocycloalkylene. In embodiments, L¹³ is an unsubstituted C₆-C₂₀arylene. In embodiments, L¹³ is an unsubstituted 5 to 20 memberedheteroarylene. In embodiments, L¹³ is a substituted or unsubstitutedC₁-C₁₄ alkylene. In embodiments, L¹³ is a substituted or unsubstituted 2to 14 membered heteroalkylene. In embodiments, L¹³ is a substituted orunsubstituted C₃-C₁₄ cycloalkylene. In embodiments, L¹³ is a substitutedor unsubstituted 3 to 14 membered heterocycloalkylene. In embodiments,L¹³ is a substituted or unsubstituted C₆-C₁₄ arylene. In embodiments,L¹³ is a substituted or unsubstituted 5 to 14 membered heteroarylene. Inembodiments, L¹³ is a substituted C₁-C₁₄ alkylene. In embodiments, L¹³is a substituted 2 to 14 membered heteroalkylene. In embodiments, L¹³ isa substituted C₃-C₁₄ cycloalkylene. In embodiments, L¹³ is a substituted3 to 14 membered heterocycloalkylene. In embodiments, L¹³ is asubstituted C₆-C₁₄ arylene. In embodiments, L¹³ is a substituted 5 to 14membered heteroarylene. In embodiments, L¹³ is an unsubstituted C₁-C₁₄alkylene. In embodiments, L¹³ is an unsubstituted 2 to 14 memberedheteroalkylene. In embodiments, L¹³ is an unsubstituted C₃-C₁₄cycloalkylene. In embodiments, L¹³ is an unsubstituted 3 to 14 memberedheterocycloalkylene. In embodiments, L¹³ is an unsubstituted C₆-C₁₄arylene. In embodiments, L¹³ is an unsubstituted 5 to 14 memberedheteroarylene. In embodiments, L¹³ is a substituted or unsubstitutedC₁-C₈ alkylene. In embodiments, L¹³ is a substituted or unsubstituted 2to 8 membered heteroalkylene. In embodiments, L¹³ is a substituted orunsubstituted C₃-C₈ cycloalkylene. In embodiments, L¹³ is a substitutedor unsubstituted 3 to 8 membered heterocycloalkylene. In embodiments,L¹³ is a substituted or unsubstituted C₆-C₁₀ arylene. In embodiments,L¹³ is a substituted or unsubstituted 5 to 10 membered heteroarylene. Inembodiments, L¹³ is a substituted C₁-C₈ alkylene. In embodiments, L¹³ isa substituted 2 to 8 membered heteroalkylene. In embodiments, L¹³ is asubstituted C₃-C₈ cycloalkylene. In embodiments, L¹³ is a substituted 3to 8 membered heterocycloalkylene. In embodiments, L¹³ is a substitutedC₆-C₁₀ arylene. In embodiments, L¹³ is a substituted 5 to 10 memberedheteroarylene. In embodiments, L¹³ is an unsubstituted C₁-C₈ alkylene.In embodiments, L¹³ is an unsubstituted 2 to 8 membered heteroalkylene.In embodiments, L¹³ is an unsubstituted C₃-C₈ cycloalkylene. Inembodiments, L¹³ is an unsubstituted 3 to 8 memberedheterocycloalkylene. In embodiments, L¹³ is an unsubstituted C₆-C₁₀arylene. In embodiments, L¹³ is an unsubstituted 5 to 10 memberedheteroarylene. In embodiments, L¹³ includes a substituted orunsubstituted cyclooctynyl. In embodiments, L¹³ includes a substitutedcyclooctenyl. In embodiments, L¹³ includes a product of a clickchemistry reaction. In embodiments, L¹³ includes a product of a clickchemistry reaction including the product of the reaction of acyclooctyne and an azide.

In embodiments, L¹⁴ is

In embodiments, L¹⁴ is

In embodiments, L¹ is

In embodiments, L¹⁴ is

In embodiments, L¹⁴ is

In embodiments, L¹⁴ is

In embodiments, L¹⁴ is

In embodiments, L¹⁴ is

In embodiments, L¹⁴ is

In embodiments, L¹⁴ is

In embodiments, L¹⁴ is

In embodiments, L¹⁴ is

In embodiments, L¹⁴ is

In embodiments L¹⁴ is

In embodiments, L¹⁴ is

In embodiments, L¹⁴ is

In embodiments, L¹⁴ is —NHC(O)—(CH₂)_(W)—NHC(O)O—(CH₂)_(Y1)—. Inembodiments, L¹⁴ is —NHC(O)—(CH₂)_(W)—C(O)NH—(CH₂)_(Y1)—. Inembodiments, L¹⁴ is —NHC(O)—(CH₂)_(W)—C(O)—. In embodiments, L¹⁴ is—NHC(O)—(CH₂)_(W)—NH—. In embodiments, L¹⁴ is —NHC(O)—(CH₂)_(W)—NHC(O)—.In embodiments, L¹⁴ is —NHC(O)—(CH₂)_(W)—C(O)NH—. In embodiments, L¹⁴ is—NHC(O)—(CH₂)_(W)—NHC(O)O—. In embodiments, L¹⁴ is—NHC(O)—(CH₂)_(W)—(OCH₂CH₂)_(T1)—C(O)NH—(CH₂)_(Y1)—. In embodiments, L¹⁴is —NHC(O)—(CH₂)_(W)—(OCH₂CH₂)_(T1)—C(O)NH—(CH₂)_(Y1)—C(O)—. Inembodiments, L¹⁴ is a substituted or unsubstituted C₁-C₂₀ alkylene. Inembodiments, L¹⁴ is a substituted or unsubstituted 2 to 20 memberedheteroalkylene. In embodiments, L¹⁴ is a substituted or unsubstitutedC₃-C₂₀ cycloalkylene. In embodiments, L¹⁴ is a substituted orunsubstituted 3 to 20 membered heterocycloalkylene. In embodiments, L¹⁴is a substituted or unsubstituted C₆-C₂₀ arylene. In embodiments, L¹⁴ isa substituted or unsubstituted 5 to 20 membered heteroarylene. Inembodiments, L¹⁴ is a substituted C₁-C₂₀ alkylene. In embodiments, L¹⁴is a substituted 2 to 20 membered heteroalkylene. In embodiments, L¹⁴ isa substituted C₃-C₂₀ cycloalkylene. In embodiments, L¹⁴ is a substituted3 to 20 membered heterocycloalkylene. In embodiments, L¹⁴ is asubstituted C₆-C₂₀ arylene. In embodiments, L¹⁴ is a substituted 5 to 20membered heteroarylene. In embodiments, L¹⁴ is an unsubstituted C₁-C₂₀alkylene. In embodiments, L¹⁴ is an unsubstituted 2 to 20 memberedheteroalkylene. In embodiments, L¹⁴ is an unsubstituted C₃-C₂₀cycloalkylene. In embodiments, L¹⁴ is an unsubstituted 3 to 20 memberedheterocycloalkylene. In embodiments, L¹⁴ is an unsubstituted C₆-C₂₀arylene. In embodiments, L¹⁴ is an unsubstituted 5 to 20 memberedheteroarylene. In embodiments, L¹⁴ is a substituted or unsubstitutedC₁-C₁₄ alkylene. In embodiments, L¹⁴ is a substituted or unsubstituted 2to 14 membered heteroalkylene. In embodiments, L¹⁴ is a substituted orunsubstituted C₃-C₁₄ cycloalkylene. In embodiments, L¹⁴ is a substitutedor unsubstituted 3 to 14 membered heterocycloalkylene. In embodiments,L¹⁴ is a substituted or unsubstituted C₆-C₁₄ arylene. In embodiments,L¹⁴ is a substituted or unsubstituted 5 to 14 membered heteroarylene. Inembodiments, L¹⁴ is a substituted C₁-C₁₄ alkylene. In embodiments, L¹⁴is a substituted 2 to 14 membered heteroalkylene. In embodiments, L¹⁴ isa substituted C₃-C₁₄ cycloalkylene. In embodiments, L¹⁴ is a substituted3 to 14 membered heterocycloalkylene. In embodiments, L¹⁴ is asubstituted C₆-C₁₄ arylene. In embodiments, L¹⁴ is a substituted 5 to 14membered heteroarylene. In embodiments, L¹⁴ is an unsubstituted C₁-C₁₄alkylene. In embodiments, L¹⁴ is an unsubstituted 2 to 14 memberedheteroalkylene. In embodiments, L¹⁴ is an unsubstituted C₃-C₁₄cycloalkylene. In embodiments, L¹⁴ is an unsubstituted 3 to 14 memberedheterocycloalkylene. In embodiments, L¹⁴ is an unsubstituted C₆-C₁₄arylene. In embodiments, L¹⁴ is an unsubstituted 5 to 14 memberedheteroarylene. In embodiments, L¹⁴ is a substituted or unsubstitutedC₁-C₈ alkylene. In embodiments, L¹⁴ is a substituted or unsubstituted 2to 8 membered heteroalkylene. In embodiments, L¹⁴ is a substituted orunsubstituted C₃-C₈ cycloalkylene. In embodiments, L¹⁴ is a substitutedor unsubstituted 3 to 8 membered heterocycloalkylene. In embodiments,L¹⁴ is a substituted or unsubstituted C₆-C₁₀ arylene. In embodiments,L¹⁴ is a substituted or unsubstituted 5 to 10 membered heteroarylene. Inembodiments, L¹⁴ is a substituted C₁-C₈ alkylene. In embodiments, L¹⁴ isa substituted 2 to 8 membered heteroalkylene. In embodiments, L¹⁴ is asubstituted C₃-C₈ cycloalkylene. In embodiments, L¹⁴ is a substituted 3to 8 membered heterocycloalkylene. In embodiments, L¹⁴ is a substitutedC₆-C₁₀ arylene. In embodiments, L¹⁴ is a substituted 5 to 10 memberedheteroarylene. In embodiments, L¹⁴ is an unsubstituted C₁-C₈ alkylene.In embodiments, L¹⁴ is an unsubstituted 2 to 8 membered heteroalkylene.In embodiments, L¹⁴ is an unsubstituted C₃-C₈ cycloalkylene. Inembodiments, L¹⁴ is an unsubstituted 3 to 8 memberedheterocycloalkylene. In embodiments, L¹⁴ is an unsubstituted C₆-C₁₀arylene. In embodiments, L¹⁴ is an unsubstituted 5 to 10 memberedheteroarylene. In embodiments, L¹⁴ includes a substituted orunsubstituted cyclooctynyl. In embodiments, L¹⁴ includes a substitutedcyclooctenyl. In embodiments, L¹⁴ includes a product of a clickchemistry reaction. In embodiments, L¹⁴ includes a product of a clickchemistry reaction including the product of the reaction of acyclooctyne and an azide.

W is an integer between 0 and 10. W may be an integer between 1 and 10.W may be 0. W may be 1. W may be 2. W may be 3. W may be 4. W may be 5.W may be 6. W may be 7. W may be 8. W may be 9. W may be 10. Y1 is aninteger between 0 and 10. Y1 may be an integer between 1 and 10. Y1 maybe 10. Y1 may be 1. Y1 may be 2. Y1 may be 3. Y1 may be 4. Y1 may be 5.Y1 may be 6. Y1 may be 7. Y1 may be 8. Y1 may be 9. Y1 may be 10. T1 isan integer between 0 and 10. T1 may be an integer between 1 and 10. T1may be 0. T1 may be 1. T1 may be 2. T1 may be 3. T1 may be 4. T1 may be5. T1 may be 6. T1 may be 7. T1 may be 8. T1 may be 9. T1 may be 10.

In embodiments, R² is hydrogen. In embodiments, R³ is hydrogen. Inembodiments, R⁴ is hydrogen. In embodiments, R⁵ is hydrogen. Inembodiments, R⁶ is hydrogen. In embodiments, R⁷ is hydrogen. Inembodiments, R⁸ is hydrogen. In embodiments, R⁹ is hydrogen. Inembodiments, R¹¹ is hydrogen. In embodiments, R¹² is hydrogen. Inembodiments, R² is unsubstituted C₁-C₄ alkyl. In embodiments, R³ isunsubstituted C₁-C₄ alkyl. In embodiments, R⁴ is unsubstituted C₁-C₄alkyl. In embodiments, R⁵ is unsubstituted C₁-C₄ alkyl. In embodiments,R⁶ is unsubstituted C₁-C₄ alkyl. In embodiments, R⁷ is unsubstitutedC₁-C₄ alkyl. In embodiments, R⁸ is unsubstituted C₁-C₄ alkyl. Inembodiments, R⁹ is unsubstituted C₁-C₄ alkyl. In embodiments, R¹ isunsubstituted C₁-C₄ alkyl. In embodiments, R¹² is unsubstituted C₁-C₄alkyl. In embodiments, R² is C₂-C₄ alkynyl. In embodiments, R³ is C₂-C₄alkynyl. In embodiments, R⁴ is C₂-C₄ alkynyl. In embodiments, R⁵ isC₂-C₄ alkynyl. In embodiments, R⁶ is C₂-C₄ alkynyl. In embodiments, R⁷is C₂-C₄ alkynyl. In embodiments, R⁸ is C₂-C₄ alkynyl. In embodiments,R⁹ is C₂-C₄ alkynyl. In embodiments, R¹¹ is C₂-C₄ alkynyl. Inembodiments, R¹² is C₂-C₄ alkynyl.

R² may be

R³ may be

R⁴ may be

R⁵ may be

R⁶ may be

R⁷ may be

R⁸ may be

R⁹ may be

R¹¹ may be

R¹² may be

In embodiments, the compound has the formula:

L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, L⁹, L¹⁰, L¹³, L¹⁴, R², R³R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁷, and Y are as described herein (e.g. in an aspect, embodiment,example, table, figure, or claim). Ring A is a substituted orunsubstituted cycloalkylene or substituted or unsubstitutedheterocycloalkylene. Where ring A is “unsubstituted,” Ring A retains the-L¹-R¹ substituent, but is otherwise not substituted. Likewise, wherering A is “substituted,” Ring A includes one or more substituents (e.g.substituent group, size-limited substituent, or lower substituent groupas defined above) in addition to the -L¹-R¹ substituent. R¹ isindependently a hydrogen, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, a protein moiety, a detectablemoiety, a siderophore moiety, a folate moiety, or a drug moiety. L¹ isindependently a bond, —N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)O-L¹³-L¹⁴-,—O-L¹³-L¹⁴-, —S-L¹³-L¹⁴-, —OC(O)-L¹³-L¹⁴-, —OC(O)N(R¹⁷)-L¹³-L¹⁴-,—OC(O)O-L¹³-L¹⁴-, —OSO₂-L¹³-L¹⁴-, —C(O)N(R¹⁷)-L¹³-L¹⁴-,—N(R¹⁷)C(O)-L¹³-L¹⁴-, —S(O)₂N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)S(O)₂-L¹³-L¹⁴-,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, substituted or unsubstituted heteroarylene, or a bioconjugatelinker (e.g. where R¹ is, for example a biomolecule such as a proteinmoiety (e.g antibody moiety, peptide moiety, modified peptide moietysuch as peptide moiety including folate).

As described above, each L¹, L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, L⁹, L¹¹, andL¹² may be different. Where each of L¹, L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, L⁹,L¹¹, and L¹² are different, L¹³ may be referred to as L¹³¹, L¹³², L¹³³,L¹³⁴, L¹³⁵, L¹³⁶, L¹³⁷, L¹³⁸, L¹³⁹, L¹³¹¹, and L¹³¹² to refer to L¹³substituents that correlate to L¹, L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, L⁹, L¹¹,and L¹², respectively. Likewise, where each of L¹, L², L³, L⁴, L⁵, L⁶,L⁷, L⁸, L⁹, L¹¹, and L¹² are different, L¹⁴ may be referred to as L¹⁴¹,L¹⁴², L¹⁴³, L¹⁴⁴, L¹⁴⁵, L¹⁴⁶, L¹⁴⁷, L¹⁴⁸, L¹⁴⁹, L¹⁴¹¹, and L¹⁴¹² torefer to L¹⁴ substituents that correlate to L¹, L², L³, L⁴, L⁵, L⁶, L⁷,L⁸, L⁹, L¹¹, and L¹², respectively. Likewise, where each of L¹, L², L³,L⁴, L⁵, L⁶, L⁷, L⁸, L⁹, L¹¹, and L¹² are different, R¹⁷ may be referredto as R¹⁷¹, R¹⁷², R¹⁷³, R¹⁷⁴, R¹⁷⁵, R¹⁷⁶, R¹⁷⁷, R¹⁷⁸, R¹⁷⁹, R¹⁷¹¹, andR¹⁷¹² to refer to R¹⁷ substituents that correlate to L¹, L², L³, L⁴, L⁵,L⁶, L⁷, L⁸, L⁹, L¹¹, and L¹², respectively. For example, in embodiments,L¹ is a bond, —N(R¹⁷¹)-L¹³¹-L¹⁴¹-, —N(R¹⁷¹)C(O)O-L¹³¹-L¹⁴¹-,—O-L¹³¹-L¹⁴¹-, —S-L¹³¹-L¹⁴¹-, —OC(O)-L¹³¹-L¹⁴¹-, —OC(O)N(R¹⁷¹)-L¹³¹-L¹⁴¹-, —OC(O)O-L¹³¹-L¹⁴¹-, —OSO₂-L¹³¹-L¹⁴¹-,—C(O)N(R¹⁷¹)-L¹³¹-L¹⁴¹-, —N(R¹⁷¹)C(O)-L¹³¹-L¹⁴¹-,—S(O)₂N(R¹⁷¹)-L¹³¹-L¹⁴¹-, —N(R¹⁷¹)S(O)₂-L¹³¹-L¹⁴¹-, substituted orunsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene.

In embodiments, ring A is a substituted or unsubstituted divalentradical of adamantane. In embodiments, ring A is a substituted orunsubstituted adamantylene. In embodiments, ring A is an unsubstitutedadamantylene. In embodiments, ring A is a substituted or unsubstitutedcycloalkylene. In embodiments, ring A is a substituted or unsubstitutedC₃-C₂₀ cycloalkylene. In embodiments, ring A is a substituted orunsubstituted C₃-C₁₈ cycloalkylene. In embodiments, ring A is asubstituted or unsubstituted C₃-C₁₆ cycloalkylene. In embodiments, ringA is a substituted or unsubstituted C₃-C₁₄ cycloalkylene. Inembodiments, ring A is a substituted or unsubstituted C₃-C₁₂cycloalkylene. In embodiments, ring A is a substituted or unsubstitutedC₃-C₁₀ cycloalkylene. In embodiments, ring A is a substituted orunsubstituted C₆-C₁₀ cycloalkylene. In embodiments, ring A is asubstituted or unsubstituted C₈-C₁₀ cycloalkylene. In embodiments, ringA is a substituted or unsubstituted 3 to 20 memberedheterocycloalkylene. In embodiments, ring A is a substituted orunsubstituted 3 to 18 membered heterocycloalkylene. In embodiments, ringA is a substituted or unsubstituted 3 to 16 memberedheterocycloalkylene. In embodiments, ring A is a substituted orunsubstituted 3 to 14 membered heterocycloalkylene. In embodiments, ringA is a substituted or unsubstituted 3 to 12 memberedheterocycloalkylene. In embodiments, ring A is a substituted orunsubstituted 3 to 10 membered heterocycloalkylene. In embodiments, ringA is a substituted or unsubstituted 6 to 10 memberedheterocycloalkylene. In embodiments, ring A is a substituted orunsubstituted 8 to 10 membered heterocycloalkylene.

In embodiments, -L¹-R¹ is —H. In embodiments, R¹ is hydrogen. Inembodiments, R¹ is a protein moiety. In embodiments, R¹ is an antibodymoiety. In embodiments, R¹ is a drug moiety. In embodiments, R¹ is adetectable moiety. In embodiments, R¹ is a fluorescent moiety. Inembodiments, R¹ is a siderophore moiety. In embodiments, R¹ is a folatemoiety. In embodiments, R¹ is an antibody moiety. In embodiments L¹ is abond. In embodiments L¹ is —OC(O)—. In embodiments L¹ is—OC(O)NH-Ph-CH₂—. In embodiments L¹ is —OC(O)NH-Ph-CH₂—OC(O)—. Inembodiments L¹ is —NH-Ph-CH₂—. In embodiments L¹ is —NH-Ph-CH₂—OC(O)—.In embodiments L¹ is —O-Ph-CH₂—. In embodiments L¹ is —O-Ph-CH₂—OC(O)—.In embodiments, L¹ is

In embodiments, L¹ is

In embodiments, L¹ is

In embodiments, L¹ is

In embodiments, L¹ is

In embodiments, L¹ is

In embodiments, L¹ is

In embodiments, L¹ is

In embodiments, L¹ is

In embodiments, L¹ is

In embodiments, L¹ is

In embodiments, L¹ is

In embodiments, L¹ is

In embodiments, L¹ is

In embodiments, L¹ is

In embodiments, L¹ is

In embodiments, L¹ is —NHC(O)—(CH₂)_(W)—NHC(O)O—(CH₂)_(Y1)—. Inembodiments, L¹ is —NHC(O)—(CH₂)_(W)—C(O)NH—(CH₂)_(Y1)—. In embodiments,L¹ is —NHC(O)—(CH₂)_(W)—C(O)—. In embodiments, L¹ is—NHC(O)—(CH₂)_(W)—NH—. In embodiments, L¹ is —NHC(O)—(CH₂)_(W)—NHC(O)—.In embodiments, L¹ is —NHC(O)—(CH₂)_(W)—C(O)NH—. In embodiments, L¹ is—NHC(O)—(CH₂)_(W)—NHC(O)O—. In embodiments, L¹ is—NHC(O)—(CH₂)_(W)—(OCH₂CH₂)_(T1)—C(O)NH—(CH₂)_(Y1)—. In embodiments, L¹is —NHC(O)—(CH₂)_(W)—(OCH₂CH₂)_(T1)—C(O)NH—(CH₂)_(Y1)—C(O)—. Inembodiments, L¹ is a substituted or unsubstituted C₁-C₂₀ alkylene. Inembodiments, L¹ is a substituted or unsubstituted 2 to 20 memberedheteroalkylene. In embodiments, L¹ is a substituted or unsubstitutedC₃-C₂₀ cycloalkylene. In embodiments, L¹ is a substituted orunsubstituted 3 to 20 membered heterocycloalkylene. In embodiments, L¹is a substituted or unsubstituted C₆-C₂₀ arylene. In embodiments, L¹ isa substituted or unsubstituted 5 to 20 membered heteroarylene. Inembodiments, L¹ is a substituted C₁-C₂₀ alkylene. In embodiments, L¹ isa substituted 2 to 20 membered heteroalkylene. In embodiments, L¹ is asubstituted C₃-C₂₀ cycloalkylene. In embodiments, L¹ is a substituted 3to 20 membered heterocycloalkylene. In embodiments, L¹ is a substitutedC₆-C₂₀ arylene. In embodiments, L¹ is a substituted 5 to 20 memberedheteroarylene. In embodiments, L¹ is an unsubstituted C₁-C₂₀ alkylene.In embodiments, L¹ is an unsubstituted 2 to 20 membered heteroalkylene.In embodiments, L¹ is an unsubstituted C₃-C₂₀ cycloalkylene. Inembodiments, L¹ is an unsubstituted 3 to 20 memberedheterocycloalkylene. In embodiments, L¹ is an unsubstituted C₆-C₂₀arylene. In embodiments, L¹ is an unsubstituted 5 to 20 memberedheteroarylene. In embodiments, L¹ is a substituted or unsubstitutedC₁-C₁₄ alkylene. In embodiments, L¹ is a substituted or unsubstituted 2to 14 membered heteroalkylene. In embodiments, L¹ is a substituted orunsubstituted C₃-C₁₄ cycloalkylene. In embodiments, L¹ is a substitutedor unsubstituted 3 to 14 membered heterocycloalkylene. In embodiments,L¹ is a substituted or unsubstituted C₆-C₁₄ arylene. In embodiments, L¹is a substituted or unsubstituted 5 to 14 membered heteroarylene. Inembodiments, L¹ is a substituted C₁-C₁₄ alkylene. In embodiments, L¹ isa substituted 2 to 14 membered heteroalkylene. In embodiments, L¹ is asubstituted C₃-C₁₄ cycloalkylene. In embodiments, L¹ is a substituted 3to 14 membered heterocycloalkylene. In embodiments, L¹ is a substitutedC₆-C₁₄ arylene. In embodiments, L¹ is a substituted 5 to 14 memberedheteroarylene. In embodiments, L¹ is an unsubstituted C₁-C₁₄ alkylene.In embodiments, L¹ is an unsubstituted 2 to 14 membered heteroalkylene.In embodiments, L¹ is an unsubstituted C₃-C₁₄ cycloalkylene. Inembodiments, L¹ is an unsubstituted 3 to 14 memberedheterocycloalkylene. In embodiments, L¹ is an unsubstituted C₆-C₁₄arylene. In embodiments, L¹ is an unsubstituted 5 to 14 memberedheteroarylene. In embodiments, L¹ is a substituted or unsubstitutedC₁-C₈ alkylene. In embodiments, L¹ is a substituted or unsubstituted 2to 8 membered heteroalkylene. In embodiments, L¹ is a substituted orunsubstituted C₃-C₈ cycloalkylene. In embodiments, L¹ is a substitutedor unsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, L¹is a substituted or unsubstituted C₆-C₁₀ arylene. In embodiments, L¹ isa substituted or unsubstituted 5 to 10 membered heteroarylene. Inembodiments, L¹ is a substituted C₁-C₈ alkylene. In embodiments, L¹ is asubstituted 2 to 8 membered heteroalkylene. In embodiments, L¹ is asubstituted C₃-C₈ cycloalkylene. In embodiments, L¹ is a substituted 3to 8 membered heterocycloalkylene. In embodiments, L¹ is a substitutedC₆-C₁₀ arylene. In embodiments, L¹ is a substituted 5 to 10 memberedheteroarylene. In embodiments, L¹ is an unsubstituted C₁-C₈ alkylene. Inembodiments, L¹ is an unsubstituted 2 to 8 membered heteroalkylene. Inembodiments, L¹ is an unsubstituted C₃-C₈ cycloalkylene. In embodiments,L¹ is an unsubstituted 3 to 8 membered heterocycloalkylene. Inembodiments, L¹ is an unsubstituted C₆-C₁₀ arylene. In embodiments, L¹is an unsubstituted 5 to 10 membered heteroarylene. In embodiments, L¹includes a substituted or unsubstituted cyclooctynyl. In embodiments, L¹includes a substituted cyclooctenyl. In embodiments, L¹ includes aproduct of a click chemistry reaction. In embodiments, L¹ includes aproduct of a click chemistry reaction including the product of thereaction of a cyclooctyne and an azide. In embodiments, L¹ is

In embodiments, L¹ includes

W is an integer between 0 and 10. W may be an integer between 1 and 10.W may be 0. W may be 1. W may be 2. W may be 3. W may be 4. W may be 5.W may be 6. W may be 7. W may be 8. W may be 9. W may be 10. Y1 is aninteger between 0 and 10. Y1 may be an integer between 1 and 10. Y1 maybe 0. Y1 may be 1. Y1 may be 2. Y1 may be 3. Y1 may be 4. Y1 may be 5.Y1 may be 6. Y1 may be 7. Y1 may be 8. Y1 may be 9. Y1 may be 10. T1 isan integer between 0 and 10. T1 may be an integer between 1 and 10. T1may be 0. T1 may be 1. T1 may be 2. T1 may be 3. T1 may be 4. T1 may be5. T1 may be 6. T1 may be 7. T1 may be 8. T1 may be 9. T1 may be 10.

In embodiment, R¹ is a protein moiety bonded to L¹ through an N of theprotein moiety. In embodiment, R¹ is a protein moiety bonded to L¹through an O of the protein moiety. In embodiment, R¹ is a proteinmoiety bonded to L¹ through an S of the protein moiety. In embodiment,R¹ is a protein moiety bonded to L¹ through an O of a —OC(O)— of theprotein moiety. In embodiment, R¹ is a detectable moiety. In embodiment,R¹ is a detectable moiety bonded to L¹ through an N of the detectablemoiety. In embodiment, R¹ is a detectable moiety bonded to L¹ through anO of the detectable moiety. In embodiment, R¹ is a detectable moietybonded to L¹ through an S of the detectable moiety. In embodiment, R¹ isa detectable moiety bonded to L¹ through an O of a —OC(O)— of thedetectable moiety. In embodiment, R¹ is a drug moiety. In embodiment, R¹is a drug moiety bonded to L¹ through an N of the drug moiety. Inembodiment, R¹ is a drug moiety bonded to L¹ through an O of the drugmoiety. In embodiment, R¹ is a drug moiety bonded to L¹ through an S ofthe drug moiety. In embodiment, R¹ is a drug moiety bonded to L¹ throughan O of a —OC(O)— of the drug moiety. In embodiments, R¹ isunsubstituted C₁-C₄ alkyl. In embodiments, R¹ is unsubstituted C₂-C₄alkynyl. In embodiment, R¹ is a siderophore moiety. In embodiment, R¹ isa siderophore moiety bonded to L¹ through an N of the siderophoremoiety. In embodiment, R¹ is a siderophore moiety bonded to L¹ throughan O of the siderophore moiety. In embodiment, R¹ is a siderophoremoiety bonded to L¹ through an S of the siderophore moiety. Inembodiment, R¹ is a siderophore moiety bonded to L¹ through an O of a—OC(O)— of the siderophore moiety. In embodiments, R¹ is a ligand for areceptor. In embodiments, R¹ is a receptor. In embodiments, R¹ is achelator (e.g., metal chelator, iron chelator). In embodiments, R¹ isindependently a hydrogen, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, a protein moiety, a detectablemoiety, or a drug moiety. In embodiments, R¹ is

In embodiments R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is

In embodiments, R¹ is H

In embodiments, R¹ is

In embodiments, R¹ is

R¹ may be

In embodiments, R¹ is folate. In embodiments, R¹ is a folate moiety. Inembodiments, R¹ is a folate derivative. In embodiments, R¹ is a folatederivative moiety. In embodiments, R¹ is a siderophore. In embodiments,R¹ is a siderophore moiety.

In embodiments, the compound has the formula:

L¹, L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, L⁹, L¹⁰, L¹³, L¹⁴, R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, and R¹⁷ are as described herein (e.g. in an aspect,embodiment, example, table, figure, or claim).

In embodiments, L², L³, L⁵, L⁶, L⁷, L⁸, L⁹, L¹¹, and L¹² are each abond; R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹, and R¹² are each hydrogen; L¹⁰ is—CH₂—; L⁴ is a bond, —N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)O-L¹³-L¹⁴-,—O-L¹³-L¹⁴-, —S-L¹³-L¹⁴-, —OC(O)-L¹³-L¹⁴-, —OC(O)N(R¹⁷)-L¹³-L¹⁴-,—OC(O)O-L¹³-L¹⁴-, —OSO₂-L¹³-L¹⁴-, —C(O)N(R¹⁷)-L¹³-L¹⁴-,—N(R¹⁷)C(O)-L¹³-L¹⁴-, —S(O)₂N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)S(O)₂-L¹³-L¹⁴-; andR⁴ is a protein moiety, drug moiety, or a detectable moiety. Inembodiments L⁴ is a bond, —OC(O)—, —OC(O)NH-Ph-CH₂—,—OC(O)NH-Ph-CH₂—OC(O)—, —NH-Ph-CH₂—, —NH-Ph-CH₂—OC(O)—, —O-Ph-CH₂—, or—O-Ph-CH₂—OC(O)—. In embodiment, R⁴ is independently a protein moiety.In embodiment, R⁴ is independently a drug moiety. In embodiment, R⁴ isindependently a detectable moiety.

In embodiments, L², L³, L⁵, L⁷, L⁸, L⁹, L¹¹, and L¹² are each a bond;R², R³, R⁵, R⁷, R⁸, R⁹, R¹¹, and R¹² are each hydrogen; L⁴ and L⁶ areindependently a bond, —N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)O-L¹³-L¹⁴-,—O-L¹³-L¹⁴-, —S-L¹³-L¹⁴-, —OC(O)-L¹³-L¹⁴-, —OC(O)N(R¹⁷)-L¹³-L¹⁴-,—OC(O)O-L¹³-L¹⁴-, —OSO₂-L¹³-L¹⁴-, —C(O)N(R¹⁷)-L¹³-L¹⁴-,—N(R¹⁷)C(O)-L¹³-L¹⁴-, —S(O)₂N(R¹⁷)-L¹³-L¹⁴-, or —N(R¹⁷)S(O)₂-L¹³-L¹⁴-;and R⁴ and R⁶ are each independently a drug moiety, protein moiety, ordetectable moiety. In embodiments L⁴ is a bond, —OC(O)—,—OC(O)NH-Ph-CH₂—, —OC(O)NH-Ph-CH₂—OC(O)—, —NH-Ph-CH₂—,—NH-Ph-CH₂—OC(O)—, —O-Ph-CH₂—, or —O-Ph-CH₂—OC(O)—. In embodiment, R⁴ isindependently a protein moiety. In embodiment, R⁴ is independently adrug moiety. In embodiment, R⁴ is independently a detectable moiety. Inembodiments L⁶ is a bond, —OC(O)—, —OC(O)NH-Ph-CH₂—,—OC(O)NH-Ph-CH₂—OC(O)—, —NH-Ph-CH₂—, —NH-Ph-CH₂—OC(O)—, —O-Ph-CH₂—, or—O-Ph-CH₂—OC(O)—. In embodiment, R⁶ is independently a protein moiety.In embodiment, R⁶ is independently a drug moiety. In embodiment, R⁶ isindependently a detectable moiety.

In embodiments, L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, L⁹, and L¹² are each a bond;R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹² are each hydrogen; L¹⁰ is—N(-L¹¹-R¹¹)—; L¹¹ is a bond, —N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)O-L¹³-L¹⁴-,—O-L¹³-L¹⁴-, —S-L¹³-L¹⁴-, —OC(O)-L¹³-L¹⁴-, —OC(O)N(R¹⁷)-L¹³-L¹⁴-,—OC(O)O-L¹³-L¹⁴-, —OSO₂-L¹³-L¹⁴-, —C(O)N(R¹⁷)-L¹³-L¹⁴-,—N(R¹⁷)C(O)-L¹³-L¹⁴-, —S(O)₂N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)S(O)₂-L¹³-L¹⁴-; andR¹¹ is a drug moiety, protein moiety, or detectable moiety. Inembodiments L¹¹ is a bond, —OC(O)—, —OC(O)NH-Ph-CH₂—,—OC(O)NH-Ph-CH₂—OC(O)—, —NH-Ph-CH₂—, —NH-Ph-CH₂—OC(O)—, —O-Ph-CH₂—, or—O-Ph-CH₂—OC(O)—. In embodiment, R¹¹ is independently a protein moiety.In embodiment, R¹¹ is independently a drug moiety. In embodiment, R¹¹ isindependently a detectable moiety.

In embodiments, L², L³, L⁵, L⁶, L⁷, L⁸, L⁹, L¹¹, and L¹² are each abond; R², R³, R⁵, R⁷, R⁸, R⁹, and R¹² are each hydrogen; L¹⁰ is—CH(—R¹¹)—; R⁶ and R¹¹ are joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; L⁴ isa bond, —N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)O-L¹³-L¹⁴-, —O-L¹³-L¹⁴-,—S-L¹³-L¹⁴-, —OC(O)-L¹³-L¹⁴-, —OC(O)N(R¹⁷)-L¹³-L¹⁴-, —OC(O)O-L¹³-L¹⁴-,—OSO₂-L¹³-L¹⁴-, —C(O)N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)-L¹³-L¹⁴-,—S(O)₂N(R¹⁷)-L¹³-L¹⁴-, or —N(R¹⁷)S(O)₂-L¹³-L¹⁴-; and R⁴ is a drugmoiety, protein moiety, or detectable moiety. In embodiments, R⁶ and R¹¹are joined to form an unsubstituted aryl (it is understood that theunsubstituted aryl is a fused ring that does not include additionalsubstituents beyond the fused ring). In embodiments, R⁶ and R¹ arejoined to form an unsubstituted phenyl. In embodiments L⁴ is a bond,—OC(O)—, —OC(O)NH-Ph-CH₂—, —OC(O)NH-Ph-CH₂—OC(O)—, —NH-Ph-CH₂—,—NH-Ph-CH₂—OC(O)—, —O-Ph-CH₂—, or —O-Ph-CH₂—OC(O)—. In embodiment, R⁴ isindependently a protein moiety. In embodiment, R⁴ is independently adrug moiety. In embodiment, R⁴ is independently a detectable moiety.

In embodiments, L², L³, L⁴, L⁶, L⁷, L⁸, L⁹, L¹¹, and L¹² are each abond; R², R³, R⁴, R⁶, R⁷, R⁸, R⁹, R¹¹, and R¹² are each hydrogen; L¹⁰ is—CH₂—; L⁵ is a bond, —N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)O-L¹³-L¹⁴-,—O-L¹³-L¹⁴-, —S-L¹³-L¹⁴-, —OC(O)-L¹³-L¹⁴-, —OC(O)N(R¹⁷)-L¹³-L¹⁴-,—OC(O)O-L¹³-L¹⁴-, —OSO₂-L¹³-L¹⁴-, —C(O)N(R¹⁷)-L¹³-L¹⁴-,—N(R¹⁷)C(O)-L¹³-L¹⁴-, —S(O)₂N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)S(O)₂-L¹³-L¹⁴-; andR⁵ is a protein moiety, drug moiety, or a detectable moiety. Inembodiments L⁵ is a bond, —OC(O)—, —OC(O)NH-Ph-CH₂—,—OC(O)NH-Ph-CH₂—OC(O)—, —NH-Ph-CH₂—, —NH-Ph-CH₂—OC(O)—, —O-Ph-CH₂—, or—O-Ph-CH₂—OC(O)—. In embodiment, R⁵ is independently a protein moiety.In embodiment, R⁵ is independently a drug moiety. In embodiment, R⁵ isindependently a detectable moiety.

In embodiments, L², L³, L⁴, L⁶, L⁸, L⁹, L¹¹, and L¹² are each a bond;R², R³, R⁴, R⁶, R⁸, R⁹, R¹¹, and R¹² are each hydrogen; L⁵ and L⁷ areindependently a bond, —N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)O-L¹³-L¹⁴-,—O-L¹³-L¹⁴-, —S-L¹³-L¹⁴-, —OC(O)-L¹³-L¹⁴-, —OC(O)N(R¹⁷)-L¹³-L¹⁴-,—OC(O)O-L¹³-L¹⁴-, —OSO₂-L¹³-L¹⁴-, —C(O)N(R¹⁷)-L¹³-L¹⁴-,—N(R¹⁷)C(O)-L¹³-L¹⁴-, —S(O)₂N(R¹⁷)-L¹³-L¹⁴-, or —N(R¹⁷)S(O)₂-L¹³-L¹⁴-;and R⁵ and R⁷ are each independently a drug moiety, protein moiety, ordetectable moiety. In embodiments L⁵ is a bond, —OC(O)—,—OC(O)NH-Ph-CH₂—, —OC(O)NH-Ph-CH₂—OC(O)—, —NH-Ph-CH₂—,—NH-Ph-CH₂—OC(O)—, —O-Ph-CH₂—, or —O-Ph-CH₂—OC(O)—. In embodiment, R⁵ isindependently a protein moiety. In embodiment, R⁵ is independently adrug moiety. In embodiment, R⁵ is independently a detectable moiety. Inembodiments L⁷ is a bond, —OC(O)—, —OC(O)NH-Ph-CH₂—,—OC(O)NH-Ph-CH₂—OC(O)—, —NH-Ph-CH₂—, —NH-Ph-CH₂—OC(O)—, —O-Ph-CH₂—, or—O-Ph-CH₂—OC(O)—. In embodiment, R⁷ is independently a protein moiety.In embodiment, R⁷ is independently a drug moiety. In embodiment, R⁷ isindependently a detectable moiety.

In embodiments, L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, L⁹, and L¹² are each a bond;R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹² are each hydrogen; L¹⁰ is—N(-L¹¹-R¹¹)—; L¹¹ is a bond, —N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)O-L¹³-L¹⁴-,—O-L¹³-L¹⁴-, —S-L¹¹-L¹⁴-, —OC(O)-L¹³-L¹⁴-, —OC(O)N(R¹⁷)-L¹³-L¹⁴-,—OC(O)O-L¹³-L¹⁴-, —OSO₂-L¹³-L¹⁴-, —C(O)N(R¹⁷)-L¹³-L¹⁴-,—N(R¹⁷)C(O)-L¹³-L¹⁴-, —S(O)₂N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)S(O)₂-L¹³-L¹⁴-; andR¹¹ is a drug moiety, protein moiety, or detectable moiety. Inembodiments L¹¹ is a bond, —OC(O)—, —OC(O)NH-Ph-CH₂—,—OC(O)NH-Ph-CH₂—OC(O)—, —NH-Ph-CH₂—, —NH-Ph-CH₂—OC(O)—, —O-Ph-CH₂—, or—O-Ph-CH₂—OC(O)—. In embodiment, R¹¹ is independently a protein moiety.In embodiment, R¹¹ is independently a drug moiety. In embodiment, R¹¹ isindependently a detectable moiety.

In embodiments, L², L³, L⁴, L⁶, L⁷, L⁸, L⁹, L¹¹, and L¹² are each abond; R², R³, R⁴, R⁶, R⁸, R⁹, and R¹² are each hydrogen; L¹⁰ is—CH(—R¹¹)—; R⁷ and R¹¹ are joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; L⁵ isa bond, —N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)O-L¹³-L¹⁴-, —O-L¹³-L¹⁴-,—S-L¹³-L¹⁴-, —OC(O)-L¹³-L¹⁴-, —OC(O)N(R¹⁷)-L¹³-L¹⁴-, —OC(O)O-L¹³-L¹⁴-,—OSO₂-L¹³-L¹⁴-, —C(O)N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)-L¹³-L¹⁴-,—S(O)₂N(R¹⁷)-L¹³-L¹⁴-, or —N(R¹⁷)S(O)₂-L¹³-L¹⁴-; and R⁵ is a drugmoiety, protein moiety, or detectable moiety. In embodiments, R⁷ and R¹¹are joined to form an unsubstituted aryl (it is understood that theunsubstituted aryl is a fused ring that does not include additionalsubstituents beyond the fused ring). In embodiments, R⁷ and R¹¹ arejoined to form an unsubstituted phenyl. In embodiments L⁵ is a bond,—OC(O)—, —OC(O)NH-Ph-CH₂—, —OC(O)NH-Ph-CH₂—OC(O)—, —NH-Ph-CH₂—,—NH-Ph-CH₂—OC(O)—, —O-Ph-CH₂—, or —O-Ph-CH₂—OC(O)—. In embodiment, R⁵ isindependently a protein moiety. In embodiment, R⁵ is independently adrug moiety. In embodiment, R⁵ is independently a detectable moiety.

In embodiments, the drug moiety is independently a monovalent radical ofan anti-infective agent. In embodiments, the anti-infective agent is ananti-parasitic drug. In embodiments, the anti-infective agent is ananti-bacterial drug. In embodiments, the anti-infective agent is ananti-malarial drug. In embodiments, the drug moiety is independently amonovalent radical of an anti-cancer agent. In embodiments, thedetectable moiety is independently a monovalent radical of afluorophore. In embodiments, the protein moiety is independently amonovalent radical of an antibody. In embodiments, the drug moiety is amonovalent radical of an anti-cancer agent described herein having an N,O, S, or OC(O) group capable of binding the prodrug moiety (e.g.component of the compounds described herein not including a drug moiety,detectable moiety, or protein moiety). In embodiments, the drug moietyis a monovalent radical of an anti-infective agent described hereinhaving an N, O, S, or OC(O) group capable of binding the prodrug moiety(e.g. component of the compounds described herein not including a drugmoiety, detectable moiety, or protein moiety).

In embodiments, the drug moiety is a moiety of a pyrrolo benzodiazepine(e.g. tomaymycin), carboplatin, CC-1065, CC-1065 analog (e.g.amino-CBIs), nitrogen mustard (such as chlorambucil or melphalan),phosphoroamidate mustard, combretastatin, combretastatin analog,puromycin, centanamycin, gemcitabine, dolastatin, dolastatin analog(including auristatin (e.g. monomethyl auristatin E), anthracyclineantibiotic (such as doxorubicin, daunorubicin), a duocarmycin,duocarmycin analog, enediynes (such as neocarzinostatin orcalicheamicins), leptomycin derivaties, maytansinoid, maytansinoidanalog (e.g. mertansine), methotrexate, mitomycin C, a taxoid, a vincaalkaloid (such as vinblastine or vincristine), epothilones,camptothecin, camptothecin analog, topotecan, or irinotecan.

In embodiments, the drug moiety is a moiety of amodiaquine, atovaquone,chloroquine, clardribine, clindamycin, cytarabine, daunorubicin,docetaxel, doxorubicin, doxycycline, etoposide, fansidar, fludarabine,halofantrine, idarubicin, imiquimod, irinotecan, mefloquine,methotrexate, mitomycin, oxamniquine, paclitaxel, plicamycin,primaquine, proquanil, pyrimethamine, quinidine, quinine, topotecan,vinblastine, vincristine, KA609, KAF 156, tafenoquine, or pyronaridine.In embodiments, the drug moiety is a moiety of an anti-bacterial agentdescribed herein. In embodiments, the drug moiety is a moiety of ananti-cancer agent described herein. In embodiments, the drug moiety is amoiety of an antibody or antigen-binding fragment thereof describedherein. In embodiments, the drug moiety is a moiety of an anti-malarialagent described herein.

In some embodiments, the agent moiety (e.g. drug moiety, detectablemoiety, protein moiety) that forms part of the prodrug is chemicallychanged under physiological conditions to form an agent (e.g. drug,detectable agent, protein) selected from an anti-cancer agent oranti-infective agent (e.g. antibiotic, anti-parasitic agent, anti-viralagent), detectable agent (e.g. fluorescent agent), or protein (e.g.antibody). Examples of agents include amodiaquine, mefloquine,chloroquine, primaquine, imiquimod, oxamniquine, doxycycline,clindamycin, quinine, quinidine, halofantrine, artesunate, fansidar,atovaquone, pyrimethamine, proguanil, vinblastine, vincristine,daunorubicin, docetaxel, paclitaxel, irinotecan, etoposide, doxorubicin,idarubicin, mitomycin, plicamycin, topotecan, clardribine, cytarabine,fludarabine, and methotrexate. In some embodiments, the agent (e.g.drug, detectable agent, protein) moiety that forms part of the prodrugis a moiety as described herein.

In embodiments, the detectable moiety is a moiety of a fluorescentprotein, a xanthene derivative (e.g. fluorescein, rhodamine, Oregongreen, eosin, or Texas red), cyanine, a cyanine derivative (e.g.cyanine, indocarbocyanine, oxacarbocyanine, thiacarbocyanine ormerocyanine), a napththalene derivative (e.g. dansyl or prodan orderivatives), coumarin, a coumarin derivative, an oxadiazole derivative(e.g. pyridyloxazole, nitrobenzoxadiazole or benzoxadiazole), ananthracene derivative (e.g. anthraquinones, DRAQ5, DRAQ7, or CyTRAKOrange), a pyrene derivative (e.g. cascade blue and derivatives), anoxazine derivative (e.g. Nile red, Nile blue, cresyl violet, oxazine170), an acridine derivative (e.g. proflavin, acridine orange, acridineyellow), am arylmethine derivative (e.g. auramine, crystal violet,malachite green), tetrapyrrole derivative (e.g. porphin, phthalocyanine,bilirubin), CF Dye™, DRAQ™, CyTRAK™, BODIPY™, an Alexa Fluor™, DyLightFluor™, Atto™, Tracy™, FluoProbes™, Abberior Dyes™, DY™ dyes, MegaStokesDyes™, Sulfo Cy™, Seta™ dyes, SeTau™ dyes, Square Dyes™, Quasar™ dyes,Cal Fluor™ dyes, SureLight Dyes™, PerCP™, Phycobilisomes™, APC™, APCXL™,RPE™, or BPE™. In embodiments, the detectable moiety is a monovalentradical of a detectable agent described herein having an N, O, S, orOC(O) group capable of binding the prodrug moiety (e.g. component of thecompounds described herein not including a drug moiety, detectablemoiety, or protein moiety). In embodiments, the detectable moiety is amoiety described herein.

In embodiments, the protein moiety is an antibody moiety. In embodimentsthe antibody moiety is a moiety of bevacizumab, cetuximab, denosumab,ipilimumab, panitumumab, trastuzumab, or catumaxomab. In embodiments,the protein moiety is a monovalent radical of a protein described hereinhaving an N, O, S, or OC(O) group capable of binding the prodrug moiety(e.g. component of the compounds described herein not including a drugmoiety, detectable moiety, or protein moiety). In embodiments, theprotein moiety is a moiety of an antibody, or an antigen-bindingfragment thereof, described herein.

In embodiments, -L¹¹-R¹¹ and -L¹²-R¹² are hydrogen. In embodiments,-L¹¹-R¹¹ is hydrogen. In embodiments, -L¹²-R¹² is hydrogen.

In embodiments, the compound is not a compound including: R¹¹ and R¹² donot independently include a drug moiety, protein moiety, or detectablemoiety; L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, and L⁹ are bonds; and R², R³, R⁴,R⁵, R⁶, R⁷, R⁸, and R⁹ are hydrogen. In embodiments, the compound is nota compound including: R¹¹ and R¹² are not independently a drug moiety,protein moiety, or detectable moiety; L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, and L⁹are bonds; and R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are hydrogen. Inembodiments, the compound is not a compound including: R¹¹ and R¹² donot independently include a drug moiety, protein moiety, or detectablemoiety; R¹⁸ and R¹⁹ are joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, proteinmoiety, detectable moiety, or drug moiety; L², L³, L⁴, L⁵, L⁶, L⁷, L⁸,and L⁹ are bonds; and R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are hydrogen.In embodiments, the compound is not a compound including: R¹¹ and R¹²are not independently a drug moiety, protein moiety, or detectablemoiety; R¹⁸ and R¹⁹ are joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, proteinmoiety, detectable moiety, or drug moiety; L², L³, L⁴, L⁵, L⁶, L⁷, L⁸,and L⁹ are bonds; and R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are hydrogen.In embodiments, the compound is not a compound including: R¹¹ and R¹² donot independently include a drug moiety, protein moiety, or detectablemoiety; R¹⁸ and R¹⁹ are joined to form an unsubstituted adamantyl; L²,L³, L⁴, L⁵, L⁶, L⁷, L⁸, and L⁹ are bonds; and R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, and R⁹ are hydrogen. In embodiments, the compound is not a compoundincluding: R¹¹ and R¹² are not independently a drug moiety, proteinmoiety, or detectable moiety; R¹⁸ and R¹⁹ are joined to form anunsubstituted adamantyl; L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, and L⁹ are bonds;and R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are hydrogen.

In embodiments, the compound is not a compound wherein R¹¹ and R¹² donot independently include a drug moiety, protein moiety, or detectablemoiety; L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, and L⁹ are bonds; and R², R³, R⁴,R⁵, R⁶, R⁷, R⁸, and R⁹ are hydrogen. In embodiments, the compound is nota compound wherein R¹¹ and R¹² are not independently a drug moiety,protein moiety, or detectable moiety; L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, and L⁹are bonds; and R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are hydrogen. Inembodiments, the compound is not a compound wherein R¹¹ and R¹² do notindependently include a drug moiety, protein moiety, or detectablemoiety; R¹⁸ and R¹⁹ are joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, proteinmoiety, detectable moiety, or drug moiety; L², L³, L⁴, L⁵, L⁶, L⁷, L⁸,and L⁹ are bonds; and R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are hydrogen.In embodiments, the compound is not a compound wherein R¹¹ and R¹² arenot independently a drug moiety, protein moiety, or detectable moiety;R¹⁸ and R¹⁹ are joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, proteinmoiety, detectable moiety, or drug moiety; L², L³, L⁴, L⁵, L⁶, L⁷, L⁸,and L⁹ are bonds; and R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are hydrogen.In embodiments, the compound is not a compound wherein R¹¹ and R¹² donot independently include a drug moiety, protein moiety, or detectablemoiety; R¹⁸ and R¹⁹ are joined to form an unsubstituted adamantyl; L²,L³, L⁴, L⁵, L⁶, L⁷, L⁸, and L⁹ are bonds; and R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, and R⁹ are hydrogen. In embodiments, the compound is not a compoundwherein R¹¹ and R¹² are not independently a drug moiety, protein moiety,or detectable moiety; R¹⁸ and R¹⁹ are joined to form an unsubstitutedadamantyl; L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, and L⁹ are bonds; and R², R³, R⁴,R⁵, R⁶, R⁷, R⁸, and R⁹ are hydrogen. In embodiments, the compound is nota compound wherein R¹¹ and R¹² do not independently include a drugmoiety, protein moiety, or detectable moiety; R¹⁸ and R¹⁹ are joined toform a substituted adamantyl; L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, and L⁹ arebonds; and R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are hydrogen. Inembodiments, the compound is not a compound wherein R¹¹ and R¹² are notindependently a drug moiety, protein moiety, or detectable moiety; R¹⁸and R¹⁹ are joined to form a substituted adamantyl; L², L³, L⁴, L⁵, L⁶,L⁷, L⁸, and L⁹ are bonds; and R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ arehydrogen.

In embodiments, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³,R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are independently oxo, halogen, —CF₃,—CCl₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —OCH₃, —OCF₃, —OCHF₂, —C(O)CH₃, R²⁰-substituted orunsubstituted alkyl, R²⁰-substituted or unsubstituted heteroalkyl,R²⁰-substituted or unsubstituted cycloalkyl, R²⁰-substituted orunsubstituted heterocycloalkyl, R²⁰-substituted or unsubstituted aryl,or R²⁰-substituted or unsubstituted heteroaryl.

Each R²⁰ is independently oxo, halogen, —CF₃, —CCl₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —OCH₃,—OCF₃, —OCHF₂, —C(O)CH₃, R²¹-substituted or unsubstituted alkyl,R²¹-substituted or unsubstituted heteroalkyl, R²¹-substituted orunsubstituted cycloalkyl, R²¹-substituted or unsubstitutedheterocycloalkyl, R²¹-substituted or unsubstituted aryl, orR²¹-substituted or unsubstituted heteroaryl.

Each R²¹ is independently oxo, halogen, —CF₃, —CCl₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —OCH₃,—OCF₃, —OCHF₂, —C(O)CH₃, R²²-substituted or unsubstituted alkyl,R²²-substituted or unsubstituted heteroalkyl, R²²-substituted orunsubstituted cycloalkyl, R²²-substituted or unsubstitutedheterocycloalkyl, R²²-substituted or unsubstituted aryl, orR²²-substituted or unsubstituted heteroaryl.

Each R²² is independently oxo, halogen, —CF₃, —CCl₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —OCH₃,—OCF₃, —OCHF₂, —C(O)CH₃, unsubstituted alkyl, unsubstituted heteroalkyl,unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstitutedaryl, or unsubstituted heteroaryl.

In embodiments, L¹, L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, L⁹, L¹⁰, L¹¹, L¹², L¹³,and L¹⁴ are independently R²³-substituted or unsubstituted alkylene,R²³-substituted or unsubstituted heteroalkylene, R²³-substituted orunsubstituted cycloalkylene, R²³-substituted or unsubstitutedheterocycloalkylene, R²³-substituted or unsubstituted arylene, orR²³-substituted or unsubstituted heteroarylene.

Each R²³ is independently oxo, halogen, —CF₃, —CCl₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —OCH₃,—OCF₃, —OCHF₂, —C(O)CH₃, R²⁴-substituted or unsubstituted alkyl,R²⁴-substituted or unsubstituted heteroalkyl, R²⁴-substituted orunsubstituted cycloalkyl, R²⁴-substituted or unsubstitutedheterocycloalkyl, R²⁴-substituted or unsubstituted aryl, orR²⁴-substituted or unsubstituted heteroaryl.

Each R²⁴ is independently oxo, halogen —CF₂, —CCl₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —S O₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —OCH₃,—OCF₃, —OCHF₂, —C(O)CH₃, R²⁵-substituted or unsubstituted alkyl,R²⁵-substituted or unsubstituted heteroalkyl, R²⁵-substituted orunsubstituted cycloalkyl, R²⁵-substituted or unsubstitutedheterocycloalkyl, R²⁵-substituted or unsubstituted aryl, orR²⁵-substituted or unsubstituted heteroaryl.

Each R²⁵ is independently oxo, halogen, —CF₃, —CCl₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —OCH₃,—OCF₃, —OCHF₂, —C(O)CH₃, unsubstituted alkyl, unsubstituted heteroalkyl,unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstitutedaryl, or unsubstituted heteroaryl.

In some embodiments, the compound is a compound described herein,including in an example or table. In embodiments, L¹, L¹, L³, L⁴, L⁵,L⁶, L⁷, L⁸, L⁹, L¹⁰, L¹¹, L¹², L¹³, L¹⁴, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²²,R²³, R²⁴ and/or R²⁵ are L¹, L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, L⁹, L¹⁰, L¹¹,L¹², L¹³, L¹⁴, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³,R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, and/or R²⁵ in anexample (e.g. in a compound of table 1, table 2).

In some embodiments, a compound as described herein may include multipleinstances of L¹³, L¹⁴, R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R²⁰, R²¹, R²², R²³, R²⁴,R²⁵, X, protein moiety, drug moiety, detectable moiety and/or othervariables. In such embodiments, each variable may optional be differentand be appropriately labeled to distinguish each group for greaterclarity. For example, where each L¹³, L¹⁴, R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R²⁰,R²¹, R²², R²³, R²⁴, R²⁵, X, protein moiety, drug moiety, and/ordetectable moiety is different, they may be referred to, for example, asL^(13.1), L^(13.2), L^(13.3), L^(13.4), L^(13.5), L^(13.6), L^(13.7),L^(13.8), L^(13.9), L^(13.10), L^(13.11), L^(13.12), L^(13.13),L^(13.14), L^(13.15), L^(13.16), L^(13.17) L^(13.18), L^(13.19),L^(13.20), L^(13.21), L^(13.22), L^(13.23), L^(13.24), L^(13.25),L^(13.26), L^(13.27), L^(13.28), L^(13.29), L^(13.30), L^(13.31),L^(13.32), L^(13.33), L^(13.34), L^(13.35), L^(13.36), L^(13.37),L^(13.38), L^(13.39), L^(13.40), L^(13.41), L^(13.42), L^(14.1),L^(14.2), L^(14.3), L^(14.4), L^(14.5), L^(14.6), L^(14.7), L^(14.8),L^(14.9), L^(14.10), L^(14.11), L^(14.12), L^(14.13), L^(14.14),L^(14.15), L^(14.16), L^(14.17), L^(14.18), L^(14.19), L^(14.20),L^(14.21), L^(14.22), L^(14.23), L^(14.24), L^(14.25), L^(14.26),L^(14.27), L^(14.28), L^(14.29), L^(14.30), L^(14.31), L^(14.32),L^(14.33), L^(14.34), L^(14.35), L^(14.36), L^(14.37), L^(14.38),L^(14.39), L^(14.40), L^(14.41), L^(14.42), R^(13.1), R^(13.2),R^(13.3), R^(13.4), R^(13.5), R^(13.6), R^(13.7), R^(13.8), R^(13.9),R^(13.10), R^(13.11), R^(13.12), R^(13.13), R^(13.14), R^(13.15),R^(13.16), R^(13.17), R^(13.18), R^(13.19), R^(13.20), R^(13.21),R^(13.22), R^(13.23), R^(13.24), R^(13.25), R^(13.26), R^(13.27),R^(13.28), R^(13.29), R^(13.30), R^(13.31), R^(13.32), R^(13.33),R^(13.34), R^(13.35), R^(13.36), R^(13.37), R^(13.38), R^(13.39),R^(13.40), R^(13.41), R^(13.42), R^(14.1), R^(14.2), R^(14.3), R^(14.4),R^(14.5), R^(14.6), R^(14.7), R^(14.8), R^(14.9), R^(14.10) R^(14.11),R^(14.12), R^(14.13), R^(14.14), R^(14.15), R^(14.16), R^(14.17),R^(14.18), R^(14.19), R^(14.20), R^(14.21), R^(14.22), R^(14.23),R^(14.24), R^(14.25), R^(14.26), R^(14.27), R^(14.28), R^(14.29),R^(14.30), R^(14.31), R^(14.32), R^(14.33), R^(14.34), R^(14.35),R^(14.36), R^(14.37), R^(14.38), R^(14.39), R^(14.40), R^(14.41),R^(14.42), R^(15.1), R^(15.2), R^(15.3), R^(15.4), R^(15.5), R^(15.6),R^(15.7), R^(15.8), R^(15.9), R^(15.10), R^(15.11), R^(15.12),R^(15.13), R^(15.14), R^(15.15), R^(15.16), R^(15.17), R^(15.18),R^(15.19), R^(15.20), R^(15.21), R^(15.22), R^(15.23), R^(15.24),R^(15.25), R^(15.26), R^(15.27), R^(15.28), R^(15.29), R^(15.30),R^(15.31), R^(15.32), R^(15.33), R^(15.34), R^(15.35), R^(15.36),R^(15.37), R^(15.38), R^(15.39), R^(15.40), R^(15.41), R^(15.42),R^(16.1), R^(16.2), R^(16.3), R^(16.4), R^(16.5), R^(16.6), R^(16.7),R^(16.8), R^(16.9), R^(16.10), R^(16.11), R^(16.12), R^(16.13),R^(16.14), R^(16.15), R^(16.16), R^(16.17), R^(16.18), R^(16.19),R^(16.20), R^(16.21), R^(16.22), R^(16.23), R^(16.24), R^(16.25),R^(16.26), R^(16.27), R^(16.28), R^(16.29), R^(16.30), R^(16.31),R^(16.32), R^(16.33), R^(16.34), R^(16.35), R^(16.36), R^(16.37),R^(16.38), R^(16.39), R^(16.40), R^(16.41), R^(16.42), R^(17.1),R^(17.2), R^(17.3), R^(17.4), R^(17.5), R^(17.6), R^(17.7), R^(17.8),R^(17.9), R^(17.10), R^(17.11), R^(17.12), R^(17.13), R^(17.14),R^(17.15), R^(17.16), R^(17.17), R^(17.18), R^(17.19), R^(17.20),R^(17.21), R^(17.22), R^(17.23), R^(17.24), R^(17.25), R^(17.26),R^(17.27), R^(17.28), R^(17.29), R^(17.30), R^(17.31), R^(17.32),R^(17.33), R^(17.34), R^(17.35), R^(17.36), R^(17.37), R^(17.38),R^(17.39), R^(17.40), R^(17.41), R^(17.42), R^(20.1), R^(20.2),R^(20.3), R^(20.4), R^(20.5), R^(20.6), R^(20.7), R^(20.8), R^(20.9),R^(20.10), R^(20.11), R^(20.12), R^(20.13), R^(20.14), R^(20.15),R^(20.16), R^(20.17), R^(20.18), R^(20.19), R^(20.20), R^(20.21),R^(20.22), R^(20.23), R^(20.24), R^(20.25), R^(20.26), R^(20.27),R^(20.28), R^(20.29), R^(20.30), R^(20.31), R^(20.32), R^(20.33),R^(20.34), R^(20.35), R^(20.36), R^(20.37), R^(20.38), R^(20.39),R^(20.40), R^(20.41), R^(20.42), R^(21.1), R^(21.2), R^(21.3), R^(21.4),R^(21.5), R^(21.6), R^(21.7), R^(21.8), R^(21.9), R^(21.10), R^(21.11),R^(21.12), R^(21.13), R^(21.14), R^(21.15), R^(21.16), R^(21.17),R^(21.18), R^(21.19), R^(21.20), R^(21.21), R^(21.22), R^(21.23),R^(21.24), R^(21.25), R^(21.26), R^(21.27), R^(21.28), R^(21.29),R^(21.30), R^(21.31), R^(21.32), R^(21.33), R^(21.34), R^(21.35),R^(21.36), R^(21.37), R^(21.38), R^(21.39), R^(21.40), R^(21.41),R^(21.42), R^(22.1), R^(22.2), R^(22.3), R^(22.4), R^(22.5), R^(22.6),R^(22.7), R^(22.8), R^(22.9), R^(22.10), R^(22.11), R^(22.12),R^(22.13), R^(22.14), R^(22.15), R^(22.16), R^(22.17), R^(22.18),R^(22.19), R^(22.20), R^(22.21), R^(22.22), R^(22.23), R^(22.24),R^(22.25), R^(22.26), R^(22.27), R^(22.28), R^(22.29), R^(22.30),R^(22.31), R^(22.32), R^(22.33), R^(22.34), R^(22.35), R^(22.36),R^(22.37), R^(22.38), R^(22.39), R^(22.40), R^(22.41), R^(22.42),X^(0.1), X^(0.2), X^(0.3), X^(0.4), X^(0.5), X^(0.6), X^(0.7), X^(0.8),X^(0.9), X^(0.10), X^(0.11), X^(0.12), X^(0.13), X^(0.14), X^(0.15),X^(0.16), X^(0.17), X^(0.18), X^(0.19), X^(0.20), X^(0.21), X^(0.22),X^(0.23), X^(0.24), X^(0.25), X^(0.26), X^(0.27), X^(0.28), X^(0.29),X^(0.30), X^(0.31), X^(0.32), X^(0.33), X^(0.34), X^(0.35), X^(0.36),X^(0.37), X^(0.38), X^(0.39), X^(0.40), X^(0.41), X^(0.42) proteinmoiety¹, protein moiety², protein moiety³, protein moiety⁴, proteinmoiety⁵, protein moiety⁶, protein moiety⁷, protein moiety⁸, proteinmoiety⁹, protein moiety¹⁰, protein moiety¹¹, protein moiety¹², proteinmoiety¹³, protein moiety¹⁴, protein moiety¹⁵, protein moiety¹⁶, proteinmoiety¹⁷, protein moiety¹⁸, protein moiety¹⁹, protein moiety²⁰, proteinmoiety²¹, protein moiety²², protein moiety²³, protein moiety²⁴, proteinmoiety²⁵, protein moiety²⁶, protein moiety²⁷, protein moiety²⁸, proteinmoiety²⁹, protein moiety³⁰, protein moiety³¹, protein moiety³², proteinmoiety³³, protein moiety³⁴, protein moiety³⁵ m protein moiety³⁶, proteinmoiety³⁷, protein moiety³⁸, protein moiety³⁹, protein moiety⁴⁰, proteinmoiety⁴¹, protein moiety⁴², drug moiety¹, drug moiety², drug moiety³,drug moiety⁴, drug moiety⁵, drug moiety⁶, drug moiety⁷, drug moiety⁸,drug moiety⁹, drug moiety¹⁰, drug moiety¹¹, drug moiety¹², drugmoiety¹³, drug moiety¹⁴, protein moiety¹⁵, drug moiety¹⁶, drug moiety¹⁷,drug moiety¹⁸, drug moiety¹⁹, drug moiety²⁰, drug moiety²¹, drugmoiety²², drug moiety²³, drug moiety²⁴, drug moiety²⁵, drug moiety²⁶,drug moiety²⁷, drug moiety²⁸, drug moiety²⁹, drug moiety³⁰, drugmoiety³¹, drug moiety³², drug moiety³³, drug moiety³⁴, drug moiety³⁵,drug moiety³⁶, drug moiety³⁷, drug moiety³⁸, drug moiety³⁹, drugmoiety⁴⁰, drug moiety⁴¹, drug moiety⁴², detectable moiety¹, detectablemoiety², detectable moiety³, detectable moiety⁴, detectable moiety⁵,detectable moiety⁶, detectable moiety⁷, detectable moiety⁸, detectablemoiety⁹, detectable moiety¹⁰, detectable moiety¹¹, detectable moiety¹²,detectable moiety¹³, detectable, detectable moiety¹⁴, detectablemoiety¹⁵, detectable moiety¹⁶, detectable moiety¹⁷, detectable moiety¹⁸,detectable moiety¹⁹, detectable moiety²⁰, detectable moiety²¹,detectable moiety²², detectable moiety²³, detectable moiety²⁴,detectable moiety²⁵, detectable moiety²⁶, detectable moiety²⁷,detectable moiety²⁸, detectable moiety²⁹, detectable moiety³⁰,detectable moiety³¹, detectable moiety³², detectable moiety³³,detectable moiety³⁴, detectable moiety³⁵, detectable moiety³⁶,detectable moiety³⁷, detectable moiety³⁸, detectable moiety³⁹,detectable moiety⁴⁰, detectable moiety⁴¹, detectable moiety⁴²,respectively, wherein the definition of L¹³ is assumed by L^(13.1),L^(13.2), L^(13.3), L^(13.4), L^(13.5), L^(13.6), L^(13.7), L^(13.8),L^(13.9), L^(13.10), L^(13.11), L^(13.12), L^(13.13), L^(13.14),L^(13.15), L^(13.16), L^(13.17), L^(13.18), L^(13.19), L^(13.20),L^(13.21) L^(13.22), L^(13.23), L^(13.24), L^(13.25), L^(13.26),L^(13.27), L^(13.28), L^(13.29), L^(13.30), L^(13.31), L^(13.32),L^(13.33), L^(13.34), L^(13.35), L^(13.36), L^(13.37), L^(13.38),L^(13.39), L^(13.40), L^(13.41), L^(13.42), the definition of L¹⁴ isassumed by L^(14.1), L^(14.2), L^(14.3), L^(14.4), L^(14.5), L^(14.6),L^(14.7), L^(14.8), L^(14.9), L^(14.10), L^(14.11), L^(14.12),L^(14.13), L^(14.14), L^(14.15), L^(14.16), L^(14.17), L^(14.18),L^(14.19), L^(14.20), L^(14.21), L^(14.22), L^(14.23), L^(14.24),L^(14.25), L^(14.26), L^(14.27), L^(14.28), L^(14.29), L^(14.30),L^(14.31), L^(14.32), L^(14.33), L^(14.34), L^(14.35), L^(14.36),L^(14.37), L^(14.38), L^(14.39), L^(14.40), L^(14.41), L^(14.42), thedefinition of R¹³ is assumed by R^(13.1), R^(13.2), R^(13.3), R^(13.4),R^(13.5), R^(13.6), R^(13.7), R^(13.8), R^(13.9), R^(13.10), R^(13.11),R^(13.12), R^(13.13), R^(13.14), R^(13.15), R^(13.16), R^(13.17),R^(13.18), R^(13.19), R^(13.20), R^(13.21), R^(13.22), R^(13.23),R^(13.24), R^(13.25), R^(13.26), R^(13.27), R^(13.28), R^(13.29),R^(13.30), R^(13.31), R^(13.32), R^(13.33), R^(13.34), R^(13.35),R^(13.36), R^(13.37), R^(13.38), R^(13.39), R^(13.40), R^(13.41),R^(13.42), the definition of R¹⁴ is assumed by R^(14.1), R^(14.2),R^(14.3), R^(14.4), R^(14.5), R^(14.6), R^(14.7), R^(14.8), R^(14.9),R^(14.10), R^(14.11), R^(14.12), R^(14.13), R^(14.14), R^(14.15),R^(14.16), R^(14.17), R^(14.18), R^(14.19), R^(14.20), R^(14.21),R^(14.22), R^(14.23), R^(14.24), R^(14.25), R^(14.26), R^(14.27),R^(14.28), R^(14.29), R^(14.30), R^(14.31), R^(14.32), R^(14.33),R^(14.34), R^(14.35), R^(14.36), R^(14.37), R^(14.38), R^(14.39),R^(14.40), R^(14.41), R^(14.42), the definition of R¹⁵ is assumed byR^(15.1), R^(15.2), R^(15.3), R^(15.4), R^(15.5), R^(15.6), R^(15.7),R^(15.8), R^(15.9), R^(15.10), R^(15.11), R^(15.12), R^(15.13),R^(15.14), R^(15.15), R^(15.16), R^(15.17), R^(15.18), R^(15.19),R^(15.20), R^(15.21), R^(15.22), R^(15.23), R^(15.24), R^(15.25),R^(15.26), R^(15.27), R^(15.28), R^(15.29), R^(15.30), R^(15.31),R^(15.32), R^(15.33), R^(15.34), R^(15.35), R^(15.36), R^(15.37),R^(15.38), R^(15.39), R^(15.40), R^(15.41), R^(15.42), the definition ofR¹⁶ is assumed by R^(16.1), R^(16.2), R^(16.3), R^(16.4), R^(16.5),R^(16.6), R^(16.7), R^(16.8), R^(16.9), R^(16.10), R^(16.11), R^(16.12),R^(16.13), R^(16.14), R^(16.15), R^(16.16), R^(16.17), R^(16.18),R^(16.19), R^(16.20), R^(16.21), R^(16.22), R^(16.23), R^(16.24),R^(16.25), R^(16.26), R^(16.27), R^(16.28), R^(16.29), R^(16.30),R^(16.31), R^(16.32), R^(16.33), R^(16.34), R^(16.35), R^(16.36),R^(16.37), R^(16.38), R^(16.39), R^(16.40), R^(16.41), R^(16.42), thedefinition of R¹⁷ is assumed by R^(17.1), R^(17.2), R^(17.3), R^(17.4),R^(17.5), R^(17.6), R^(17.7), R^(17.8), R^(17.9), R^(17.10), R^(17.11),R^(17.12), R^(17.13), R^(17.14), R^(17.15), R^(17.16), R^(17.17),R^(17.18), R^(17.19), R^(17.20), R^(17.21), R^(17.22), R^(17.23),R^(17.24), R^(17.25), R^(17.26), R^(17.27), R^(17.28), R^(17.29),R^(17.30), R^(17.31), R^(17.32), R^(17.33), R^(17.34), R^(17.35),R^(17.36), R^(17.37), R^(17.38), R^(17.39), R^(17.40), R^(17.41),R^(17.42), the definition of R²⁰ is assumed by R^(20.1), R^(20.2),R^(20.3), R^(20.4), R^(20.5), R^(20.6), R^(20.7), R^(20.8), R^(20.9),R^(20.10), R^(20.11), R^(20.12), R^(20.13), R^(20.14), R^(20.15),R^(20.16), R^(20.17), R^(20.18), R^(20.19), R^(20.20), R^(20.21),R^(20.22), R^(20.23), R^(20.24), R^(20.25), R^(20.26), R^(20.27),R^(20.28), R^(20.29), R^(20.30), R^(20.31), R^(20.32), R^(20.33),R^(20.34), R^(2.35), R^(20.36), R^(20.37), R^(20.38), R^(20.39),R^(20.40), R^(20.41), R^(20.42), the definition of R²¹ is assumed byR^(21.1), R^(21.2), R^(21.3), R^(21.4), R^(21.5), R^(21.6), R^(21.7),R^(21.8), R^(21.9), R^(21.10), R^(21.11), R^(21.12), R^(21.13),R^(21.14), R^(21.15), R^(21.16), R^(21.17), R^(21.18), R^(21.19),R^(21.20), R^(21.21), R^(21.22), R^(21.23), R^(21.24), R^(21.25),R^(21.26), R^(21.27), R^(21.28), R^(21.29), R^(21.30), R^(21.31),R^(21.32), R^(21.33), R^(21.34), R^(21.35), R^(21.36), R^(21.37),R^(21.38), R^(21.39), R^(21.40), R^(21.41), R^(21.42), the definition ofR²² is assumed by R^(22.1), R^(22.2), R^(22.3), R^(22.4), R^(22.5),R^(22.6), R^(22.7), R^(22.8), R^(22.9), R^(22.10), R^(22.11), R^(22.12),R^(22.13), R^(22.14), R^(22.15), R^(22.16), R^(22.17), R^(22.18),R^(22.19), R^(22.20), R^(22.21), R^(22.22), R^(22.23), R^(22.24),R^(22.25), R^(22.26), R^(22.27), R^(22.28), R^(22.29), R^(22.30),R^(22.31), R^(22.32), R^(22.33), R^(22.34), R^(22.35), R^(22.36),R^(22.37), R^(22.38), R^(22.39), R^(22.40), R^(22.41), R^(22.42), thedefinition of R²³ is assumed by R^(23.1), R^(23.2), R^(23.3), R^(23.4),R^(23.5), R^(23.6), R^(23.7), R^(23.8), R^(23.9), R^(23.10), R^(23.11),R^(23.12), R^(23.13), R^(23.14), R^(23.15), R^(23.16), R^(23.17),R^(23.18), R^(23.19), R^(23.20), R^(23.21), R^(23.22), R^(23.23),R^(23.24), R^(23.25), R^(23.26), R^(23.27), R^(23.28), R^(23.29),R^(23.30), R^(23.31), R^(23.32), R^(23.33), R^(23.34), R^(23.35),R^(23.36), R^(23.37), R^(23.38), R^(23.39), R^(23.40), R^(23.41),R^(23.42), the definition of R²⁴ is assumed by R^(24.1), R^(24.2),R^(24.3), R^(24.4), R^(24.5), R^(24.6), R^(24.7), R^(24.8), R^(24.9),R^(24.10), R^(24.11), R^(24.12), R^(24.13), R^(24.14), R^(24.15),R^(24.16), R^(24.17), R^(24.18), R^(24.19), R^(24.20), R^(24.21),R^(24.22), R^(24.23), R^(24.24), R^(24.25), R^(24.26), R^(24.27),R^(24.28), R^(24.29), R^(24.30), R^(24.31), R^(24.32), R^(24.33),R^(24.34), R^(24.35), R^(24.36), R^(24.37), R^(24.38), R^(24.39),R^(24.40), R^(24.41), R^(24.42), the definition of R²⁵ is assumed byR^(25.1), R^(25.2), R^(25.3), R^(25.4), R^(25.5), R^(25.6), R^(25.7),R^(25.8), R^(25.9), R^(25.10), R^(25.11), R^(25.12), R^(25.13),R^(25.14), R^(25.15), R^(25.16), R^(25.17), R^(25.18), R^(25.19),R^(25.20), R^(25.21), R^(25.22), R^(25.23), R^(25.24), R^(25.25),R^(25.26), R^(25.27), R^(25.28), R^(25.29), R^(25.30), R^(25.31),R^(25.32), R^(25.33), R^(25.34), R^(25.35), R^(25.36), R^(25.37),R^(25.38), R^(25.39), R^(25.40), R^(25.41), R^(25.42), the definition ofX is assumed by X^(0.1), X^(0.2), X^(0.3), X^(0.4), X^(0.5), X^(0.6),X^(0.7), X^(0.8), X^(0.9), X^(0.10), X^(0.11), X^(0.12), X^(0.13),X^(0.14), X^(0.15), X^(0.16), X^(0.17), X^(0.18), X^(0.19), X^(0.20),X^(0.21), X^(0.22), X^(0.23), X^(0.24), X^(0.25), X^(0.26), X^(0.27),X^(0.28), X^(0.29), X^(0.30), X^(0.31), X^(0.32), X^(0.33), X^(0.34),X^(0.35), X^(0.36), X^(0.37), X^(0.38), X^(0.39), X^(0.40), X^(0.41),X^(0.42), the definition of protein moiety is assumed by proteinmoiety¹, protein moiety², protein moiety³, protein moiety⁴, proteinmoiety⁵, protein moiety⁶, protein moiety⁷, protein moiety⁸, proteinmoiety⁹, protein moiety¹⁰, protein moiety¹¹, protein moiety¹², proteinmoiety¹³, protein moiety¹⁴, protein moiety¹⁵, protein moiety¹⁶, proteinmoiety¹⁷, protein moiety¹⁸, protein moiety¹⁹, protein moiety²⁰, proteinmoiety²¹, protein moiety²², protein moiety²³, protein moiety²⁴, proteinmoiety²⁵, protein moiety²⁶, protein moiety²⁷, protein moiety²⁸, proteinmoiety²⁹, protein moiety³⁰, protein moiety³¹, protein moiety³², proteinmoiety³³, protein moiety³⁴, protein moiety³⁵, protein moiety³⁶, proteinmoiety³⁷, protein moiety³⁸, protein moiety³⁹, protein moiety⁴⁰, proteinmoiety⁴¹, protein moiety⁴², the definition of drug moiety is assumed bydrug moiety¹, drug moiety², drug moiety³, drug moiety⁴, drug moiety⁵,drug moiety⁶, drug moiety⁷, drug moiety⁸, drug moiety⁹, drug moiety¹⁰,drug moiety¹¹, drug moiety¹², drug moiety¹³, drug moiety¹⁴, drugmoiety¹⁵, drug moiety¹⁶, drug moiety¹⁷, drug moiety¹⁸, drug moiety¹⁹,drug moiety²⁰, drug moiety²¹, drug moiety²², drug moiety²³, drugmoiety²⁴, drug moiety²⁵, drug moiety²⁶, drug moiety²⁷, drug moiety²⁸,drug moiety²⁹, drug moiety³⁰, drug moiety³¹, drug moiety³², drugmoiety³³, drug moiety³⁴, drug moiety³⁵, drug moiety³⁶, drug moiety³⁷,drug moiety³⁸, drug moiety³⁹, drug moiety⁴⁰, drug moiety⁴¹, drugmoiety⁴², the definition of detectable moiety is assumed by detectablemoiety¹, detectable moiety², detectable moiety³, detectable moiety⁴,detectable moiety⁵, detectable moiety⁶, detectable moiety⁷, detectablemoiety⁸, detectable moiety⁹, detectable moiety¹⁰, detectable moiety¹¹,detectable moiety¹², detectable moiety¹³, detectable moiety¹⁴,detectable moiety¹⁵, detectable moiety¹⁶, detectable moiety¹⁷,detectable moiety¹⁸, detectable moiety¹⁹, detectable moiety²⁰,detectable moiety²¹, detectable moiety²², detectable moiety²³,detectable moiety²⁴, detectable moiety²⁵, detectable moiety²⁶,detectable moiety²⁷, detectable moiety²⁸, detectable moiety²⁹,detectable moiety³⁰, detectable moiety³¹, detectable moiety³²,detectable moiety³³, detectable moiety³⁴, detectable moiety³⁵,detectable moiety³⁶, detectable moiety³⁷, detectable moiety³⁸,detectable moiety³⁹, detectable moiety⁴⁰, detectable moiety⁴¹,detectable moiety⁴².

The variables used within the definition of L¹³, L¹⁴, R¹³, R¹⁴, R¹⁵,R¹⁶, R¹⁷, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, X, protein moiety, drug moiety,detectable moiety, and/or other variables that appear at multipleinstances and are different may similarly be appropriately labeled todistinguish each group for greater clarity.

In embodiments, R¹ is independently hydrogen, oxo, halogen, —CF₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R²⁶-substituted or unsubstitutedalkyl, R²⁶-substituted or unsubstituted heteroalkyl, R²⁶-substituted orunsubstituted cycloalkyl, R²⁶-substituted or unsubstitutedheterocycloalkyl, R²⁶-substituted or unsubstituted aryl, orR²⁶-substituted or unsubstituted heteroaryl.

R²⁶ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R²⁷-substituted or unsubstituted alkyl, R²⁷-substituted or unsubstitutedheteroalkyl, R²⁷-substituted or unsubstituted cycloalkyl, R²⁷substituted or unsubstituted heterocycloalkyl, R²⁷-substituted orunsubstituted aryl, or R²⁷-substituted or unsubstituted heteroaryl.

R²⁷ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R²⁸-substituted or unsubstituted alkyl, R²⁸-substituted or unsubstitutedheteroalkyl, R²⁸-substituted or unsubstituted cycloalkyl,R²⁸-substituted or unsubstituted heterocycloalkyl, R²⁸-substituted orunsubstituted aryl, or R²⁸-substituted or unsubstituted heteroaryl.

In embodiments, R⁵ is independently hydrogen, oxo, halogen, —CF₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R²⁹-substituted or unsubstitutedalkylene, R²⁹-substituted or unsubstituted heteroalkylene,R²⁹-substituted or unsubstituted cycloalkylene, R²⁹ substituted orunsubstituted heterocycloalkylene, R²⁹-substituted or unsubstitutedarylene, or R²⁹-substituted or unsubstituted heteroarylene.

R²⁹ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R³⁰-substituted or unsubstituted alkyl, R³⁰-substituted or unsubstitutedheteroalkyl, R³⁰-substituted or unsubstituted cycloalkyl, R³⁰substituted or unsubstituted heterocycloalkyl, R³⁰-substituted orunsubstituted aryl, or R³⁰-substituted or unsubstituted heteroaryl.

R³⁰ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R³¹-substituted or unsubstituted alkyl, R³¹-substituted or unsubstitutedheteroalkyl, R³¹-substituted or unsubstituted cycloalkyl,R³¹-substituted or unsubstituted heterocycloalkyl, R³¹-substituted orunsubstituted aryl, or R³¹-substituted or unsubstituted heteroaryl.

In embodiments, R⁷ is independently hydrogen, oxo, halogen, —CF₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R³²-substituted or unsubstitutedalkylene, R³²-substituted or unsubstituted heteroalkylene,R³²-substituted or unsubstituted cycloalkylene, R³²-substituted orunsubstituted heterocycloalkylene, R³²-substituted or unsubstitutedarylene, or R³²-substituted or unsubstituted heteroarylene.

R³² is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R³³-substituted or unsubstituted alkyl, R³³-substituted or unsubstitutedheteroalkyl, R³³-substituted or unsubstituted cycloalkyl, R³³substituted or unsubstituted heterocycloalkyl, R³³-substituted orunsubstituted aryl, or R³³-substituted or unsubstituted heteroaryl.

R³³ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R³⁴-substituted or unsubstituted alkyl, R³⁴-substituted or unsubstitutedheteroalkyl, R³⁴-substituted or unsubstituted cycloalkyl,R³⁴-substituted or unsubstituted heterocycloalkyl, R³⁴-substituted orunsubstituted aryl, or R³⁴-substituted or unsubstituted heteroaryl.

In embodiments, R¹¹ is independently hydrogen, oxo, halogen, —CF₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R³⁵-substituted or unsubstitutedalkylene, R³⁵-substituted or unsubstituted heteroalkylene,R³⁵-substituted or unsubstituted cycloalkylene, R³⁵-substituted orunsubstituted heterocycloalkylene, R³⁵-substituted or unsubstitutedarylene, or R³⁵-substituted or unsubstituted heteroarylene.

R³⁵ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R³⁶-substituted or unsubstituted alkyl, R³⁶-substituted or unsubstitutedheteroalkyl, R³⁶-substituted or unsubstituted cycloalkyl, R³⁶substituted or unsubstituted heterocycloalkyl, R³⁶-substituted orunsubstituted aryl, or R³⁶-substituted or unsubstituted heteroaryl.

R³⁶ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R³⁷-substituted or unsubstituted alkyl, R³⁷-substituted or unsubstitutedheteroalkyl, R³⁷-substituted or unsubstituted cycloalkyl,R³⁷-substituted or unsubstituted heterocycloalkyl, R³⁷-substituted orunsubstituted aryl, or R³⁷-substituted or unsubstituted heteroaryl.

In embodiments, R¹² is independently hydrogen, halogen, —CF₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCF₃, —OCHF₂, R³⁸-substituted or unsubstituted alkyl,R³⁸-substituted or unsubstituted heteroalkyl, R³⁸-substituted orunsubstituted cycloalkyl, R³⁸-substituted or unsubstitutedheterocycloalkyl, R³⁸-substituted or unsubstituted aryl, orR³⁸-substituted or unsubstituted heteroaryl.

R³⁸ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,—S(O)₂CHCH₂, —NHS(O)₂CHCH₂, R³⁹-substituted or unsubstituted alkyl,R³⁹-substituted or unsubstituted heteroalkyl, R³⁹-substituted orunsubstituted cycloalkyl, R³⁹ substituted or unsubstitutedheterocycloalkyl, R³⁹-substituted or unsubstituted aryl, orR³⁹-substituted or unsubstituted heteroaryl.

R³⁹ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,—S(O)₂CHCH₂, —NHS(O)₂CHCH₂, R⁴⁰-substituted or unsubstituted alkyl,R⁴⁰-substituted or unsubstituted heteroalkyl, R⁴⁰-substituted orunsubstituted cycloalkyl, R⁴⁰-substituted or unsubstitutedheterocycloalkyl, R⁴⁰-substituted or unsubstituted aryl, orR⁴⁰-substituted or unsubstituted heteroaryl.

In embodiments, R¹³ is independently hydrogen, halogen, —CF₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCF₃, —OCHF₂, R⁴¹-substituted or unsubstituted alkyl,R⁴¹-substituted or unsubstituted heteroalkyl, R⁴¹-substituted orunsubstituted cycloalkyl, R⁴¹-substituted or unsubstitutedheterocycloalkyl, R⁴¹-substituted or unsubstituted aryl, orR⁴¹-substituted or unsubstituted heteroaryl.

R⁴¹ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,—S(O)₂CHCH₂, —NHS(O)₂CHCH₂, R⁴²-substituted or unsubstituted alkyl,R⁴²-substituted or unsubstituted heteroalkyl, R⁴²-substituted orunsubstituted cycloalkyl, R⁴² substituted or unsubstitutedheterocycloalkyl, R⁴²-substituted or unsubstituted aryl, orR⁴²-substituted or unsubstituted heteroaryl.

R⁴² is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,—S(O)₂CHCH₂, —NHS(O)₂CHCH₂, R⁴³-substituted or unsubstituted alkyl,R⁴³-substituted or unsubstituted heteroalkyl, R⁴³-substituted orunsubstituted cycloalkyl, R⁴³-substituted or unsubstitutedheterocycloalkyl, R⁴³-substituted or unsubstituted aryl, orR⁴³-substituted or unsubstituted heteroaryl.

In embodiments, R¹⁴ is independently hydrogen, halogen, —CF₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCF₃, —OCHF₂, R⁴⁴-substituted or unsubstituted alkyl,R⁴⁴-substituted or unsubstituted heteroalkyl, R⁴⁴-substituted orunsubstituted cycloalkyl, R⁴⁴-substituted or unsubstitutedheterocycloalkyl, R⁴⁴-substituted or unsubstituted aryl, orR⁴⁴-substituted or unsubstituted heteroaryl.

R⁴⁴ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁴⁵-substituted or unsubstituted alkyl, R⁴⁵-substituted or unsubstitutedheteroalkyl, R⁴⁵-substituted or unsubstituted cycloalkyl, R⁴⁵substituted or unsubstituted heterocycloalkyl, R⁴⁵-substituted orunsubstituted aryl, or R⁴⁵-substituted or unsubstituted heteroaryl.

R⁴⁵ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁴⁶-substituted or unsubstituted alkyl, R⁴⁶-substituted or unsubstitutedheteroalkyl, R⁴⁶-substituted or unsubstituted cycloalkyl,R⁴⁶-substituted or unsubstituted heterocycloalkyl, R⁴⁶-substituted orunsubstituted aryl, or R⁴⁶-substituted or unsubstituted heteroaryl.

In embodiments, R¹⁵ is independently hydrogen, halogen, —CF₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCF₃, —OCHF₂, R⁴⁷-substituted or unsubstituted alkyl,R⁴⁷-substituted or unsubstituted heteroalkyl, R⁴⁷-substituted orunsubstituted cycloalkyl, R⁴⁷-substituted or unsubstitutedheterocycloalkyl, R⁴⁷-substituted or unsubstituted aryl, orR⁴⁷-substituted or unsubstituted heteroaryl.

R⁴⁷ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁴⁸-substituted or unsubstituted alkyl, R⁴⁸-substituted or unsubstitutedheteroalkyl, R⁴⁸-substituted or unsubstituted cycloalkyl, R⁴⁸substituted or unsubstituted heterocycloalkyl, R⁴⁸-substituted orunsubstituted aryl, or R⁴⁸-substituted or unsubstituted heteroaryl.

R⁴⁸ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁴⁹-substituted or unsubstituted alkyl, R⁴⁹-substituted or unsubstitutedheteroalkyl, R⁴⁹-substituted or unsubstituted cycloalkyl,R⁴⁹-substituted or unsubstituted heterocycloalkyl, R⁴⁹-substituted orunsubstituted aryl, or R⁴⁹-substituted or unsubstituted heteroaryl.

In embodiments, R¹⁶ is independently hydrogen, oxo, halogen, —CF₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁵⁰-substituted or unsubstitutedalkyl, R⁵⁰-substituted or unsubstituted heteroalkyl, R⁵⁰-substituted orunsubstituted cycloalkyl, R⁵⁰-substituted or unsubstitutedheterocycloalkyl, R⁵⁰-substituted or unsubstituted aryl, orR⁵⁰-substituted or unsubstituted heteroaryl.

R⁵⁰ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁵¹-substituted or unsubstituted alkyl, R⁵¹-substituted or unsubstitutedheteroalkyl, R⁵¹-substituted or unsubstituted cycloalkyl, R⁵¹substituted or unsubstituted heterocycloalkyl, R⁵¹-substituted orunsubstituted aryl, or R⁵¹-substituted or unsubstituted heteroaryl.

R⁵¹ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁵²-substituted or unsubstituted alkyl, R⁵²-substituted or unsubstitutedheteroalkyl, R⁵²-substituted or unsubstituted cycloalkyl,R⁵²-substituted or unsubstituted heterocycloalkyl, R⁵²-substituted orunsubstituted aryl, or R⁵²-substituted or unsubstituted heteroaryl.

In embodiments, R¹⁷ is independently hydrogen, oxo, halogen, —CF₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁵³-substituted or unsubstitutedalkyl, R⁵³-substituted or unsubstituted heteroalkyl, R⁵³-substituted orunsubstituted cycloalkyl, R⁵³-substituted or unsubstitutedheterocycloalkyl, R⁵³-substituted or unsubstituted aryl, orR⁵³-substituted or unsubstituted heteroaryl.

R⁵³ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁵⁴-substituted or unsubstituted alkyl, R⁵⁴-substituted or unsubstitutedheteroalkyl, R⁵⁴-substituted or unsubstituted cycloalkyl, R⁵⁴substituted or unsubstituted heterocycloalkyl, R⁵⁴-substituted orunsubstituted aryl, or R⁵⁴-substituted or unsubstituted heteroaryl.

R⁵⁴ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁵⁵-substituted or unsubstituted alkyl, R⁵⁵-substituted or unsubstitutedheteroalkyl, R⁵⁵-substituted or unsubstituted cycloalkyl,R⁵⁵-substituted or unsubstituted heterocycloalkyl, R⁵⁵-substituted orunsubstituted aryl, or R⁵⁵-substituted or unsubstituted heteroaryl.

In embodiments, R¹⁸ is independently hydrogen, oxo, halogen, —CF₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁵⁶-substituted or unsubstitutedalkyl, R⁵⁶-substituted or unsubstituted heteroalkyl, R⁵⁶-substituted orunsubstituted cycloalkyl, R⁵⁶-substituted or unsubstitutedheterocycloalkyl, R⁵⁶-substituted or unsubstituted aryl, orR⁵⁶-substituted or unsubstituted heteroaryl.

R⁵⁶ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁵⁷-substituted or unsubstituted alkyl, R⁵⁷-substituted or unsubstitutedheteroalkyl, R⁵⁷-substituted or unsubstituted cycloalkyl, R⁵⁷substituted or unsubstituted heterocycloalkyl, R⁵⁷-substituted orunsubstituted aryl, or R⁵⁷-substituted or unsubstituted heteroaryl.

R⁵⁷ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁵⁸-substituted or unsubstituted alkyl, R⁵⁸-substituted or unsubstitutedheteroalkyl, R⁵⁸-substituted or unsubstituted cycloalkyl,R⁵⁸-substituted or unsubstituted heterocycloalkyl, R⁵⁸-substituted orunsubstituted aryl, or R⁵⁸-substituted or unsubstituted heteroaryl.

In embodiments, R¹⁹ is independently hydrogen, halogen, —CF₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCF₃, —OCHF₂, R⁵⁹-substituted or unsubstituted alkyl,R⁵⁹-substituted or unsubstituted heteroalkyl, R⁵⁹-substituted orunsubstituted cycloalkyl, R⁵⁹-substituted or unsubstitutedheterocycloalkyl, R⁵⁹-substituted or unsubstituted aryl, orR⁵⁹-substituted or unsubstituted heteroaryl.

R⁵⁹ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁶⁰-substituted or unsubstituted alkyl, R⁶⁰-substituted or unsubstitutedheteroalkyl, R⁶⁰-substituted or unsubstituted cycloalkyl,R⁶⁰-substituted or unsubstituted heterocycloalkyl, R⁶⁰-substituted orunsubstituted aryl, or R⁶⁰-substituted or unsubstituted heteroaryl.

R⁶⁰ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁶¹-substituted or unsubstituted alkyl, R⁶¹-substituted or unsubstitutedheteroalkyl, R⁶¹-substituted or unsubstituted cycloalkyl,R⁶¹-substituted or unsubstituted heterocycloalkyl, R⁶¹-substituted orunsubstituted aryl, or R⁶¹-substituted or unsubstituted heteroaryl.

In embodiments, L¹ is independently a bond, —N(R¹⁷)-L¹³-L¹⁴-,—N(R¹⁷)C(O)O-L¹³-L¹⁴-, —O-L¹³-L¹⁴-, —S-L¹³-L¹⁴-, —OC(O)-L¹³-L¹⁴-,—OC(O)N(R¹⁷)-L¹³-L¹⁴-, —OC(O)O-L¹³-L¹⁴-, —OSO₂-L¹³-L¹⁴-,—C(O)N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)-L¹³-L¹⁴-, —S(O)₂N(R¹⁷)-L¹³-L¹⁴-,—N(R¹⁷)S(O)₂-L¹³-L¹⁴-, R⁶²-substituted or unsubstituted alkylene,R⁶²-substituted or unsubstituted heteroalkylene, R⁶²-substituted orunsubstituted cycloalkylene, R⁶²⁻substituted or unsubstitutedheterocycloalkylene, R⁶²-substituted or unsubstituted arylene, orR⁶²-substituted or unsubstituted heteroarylene. L¹ may be a bond. L¹ maybe —N(R¹⁷¹)-L¹³¹-L¹⁴¹-. L¹ may be —N(R¹⁷¹)C(O)O-L¹³¹-L¹⁴¹-. L¹ may be—O-L¹³¹-L¹⁴¹-. L¹ may be —S-L¹³¹-L¹⁴¹-. L¹ may be —OC(O)-L¹³¹-L¹⁴¹-. L¹may be —OC(O)N(R¹⁷¹)-L¹³¹-L¹⁴¹-. L¹ may be —OC(O)O-L¹³¹-L¹⁴¹-. L¹ may be—OSO₂-L¹³¹-L¹⁴¹-. L¹ may be —C(O)N(R¹⁷¹)-L¹³¹-L¹⁴¹-. L¹ may be—N(R¹⁷¹)C(O)-L¹³¹-L¹⁴¹-. L¹ may be —S(O)₂N(R¹⁷¹)-L¹³¹-L¹⁴¹-. L¹ may be—N(R¹⁷¹)S(O)₂-L¹³¹-L¹⁴¹-. L¹ may be —C(O)O-L¹³¹-L¹⁴¹-. L¹ may be—SO₂-L¹³¹-L¹⁴¹-. L¹ may be —N(H)—. L¹ may be —N(H)C(O)O—. L¹ may be —O—.L¹ may be —S—. L¹ may be —OC(O)—. L¹ may be —OC(O)N(H)—. L¹ may be—OC(O)O—. L¹ may be —OSO₂—. L¹ may be —C(O)N(H)—. L¹ may be —N(H)C(O)—.L¹ may be —S(O)₂N(H)—. L¹ may be —N(H)S(O)₂—. L¹ may be —C(O)O—. L¹ maybe —SO₂—.

R⁶² is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁶³-substituted or unsubstituted alkyl, R⁶³-substituted or unsubstitutedheteroalkyl, R⁶³-substituted or unsubstituted cycloalkyl,R⁶³-substituted or unsubstituted heterocycloalkyl, R⁶³-substituted orunsubstituted aryl, or R⁶³-substituted or unsubstituted heteroaryl.

R⁶³ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁶⁴-substituted or unsubstituted alkyl, R⁶⁴-substituted or unsubstitutedheteroalkyl, R⁶⁴-substituted or unsubstituted cycloalkyl,R⁶⁴-substituted or unsubstituted heterocycloalkyl, R⁶⁴-substituted orunsubstituted aryl, or R⁶⁴-substituted or unsubstituted heteroaryl.

In embodiments, L⁵ is independently a bond, —N(R¹⁷)-L¹³-L¹⁴-,—N(R¹⁷)C(O)O-L¹³-L¹⁴-, —O-L¹³-L¹⁴-, —S-L¹³-L¹⁴-, —OC(O)-L¹³-L¹⁴-,—OC(O)N(R¹⁷)-L¹³-L¹⁴-, —OC(O)O-L¹³-L¹⁴-, —OSO₂-L¹³-L¹⁴-,—C(O)N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)-L¹³-L¹⁴-, —S(O)₂N(R¹⁷)-L¹³-L¹⁴-,—N(R¹⁷)S(O)₂-L¹³-L¹⁴-, R⁶⁵-substituted or unsubstituted alkylene,R⁶⁵-substituted or unsubstituted heteroalkylene, R⁶⁵-substituted orunsubstituted cycloalkylene, R⁶⁵ substituted or unsubstitutedheterocycloalkylene, R⁶⁵-substituted or unsubstituted arylene, orR⁶⁵-substituted or unsubstituted heteroarylene. L⁵ may be a bond. L⁵ maybe —N(R¹⁷⁵)-L¹³⁵-L¹⁴⁵-. L⁵ may be —N(R¹⁷⁵)C(O)O-L¹³⁵-L¹⁴⁵-. L⁵ may be—O-L¹³⁵-L¹⁴⁵-. L⁵ may be —S-L¹³⁵-L¹⁴⁵-. L⁵ may be —OC(O)-L¹³⁵-L¹⁴⁵-. L⁵may be —OC(O)N(R¹⁷⁵)-L¹³⁵-L¹⁴⁵-. L⁵ may be —OC(O)O-L¹³⁵-L¹⁴⁵-. L⁵ may be—OSO₂-L¹³⁵-L¹⁴⁵-. L⁵ may be —C(O)N(R¹⁷⁵)-L¹³⁵-L¹⁴⁵-. L⁵ may be—N(R¹⁷⁵)C(O)-L¹³⁵-L¹⁴⁵-. L⁵ may be —S(O)₂N(R¹⁷⁵)-L¹³⁵-L¹⁴⁵-. L⁵ may be—N(R¹⁷⁵)S(O)₂-L¹³⁵-L¹⁴⁵-. L⁵ may be —C(O)O-L¹³⁵-L¹⁴⁵-. L⁵ may be—SO₂-L¹³⁵-L¹⁴⁵-. L⁵ may be —N(H)—. L⁵ may be —N(H)C(O)O—. L⁵ may be —O—.L⁵ may be —S—. L⁵ may be —OC(O)—. L⁵ may be —OC(O)N(H)—. L⁵ may be—OC(O)O—. L⁵ may be —OSO₂—. L⁵ may be —C(O)N(H)—. L⁵ may be —N(H)C(O)—.L⁵ may be —S(O)₂N(H)—. L⁵ may be —N(H)S(O)₂—. L⁵ may be —C(O)O—. L⁵ maybe —SO₂—.

R⁶⁵ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₇NH₇, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁶⁶-substituted or unsubstituted alkyl, R⁶⁶-substituted or unsubstitutedheteroalkyl, R⁶⁶-substituted or unsubstituted cycloalkyl,R⁶⁶-substituted or unsubstituted heterocycloalkyl, R⁶⁶-substituted orunsubstituted aryl, or R⁶⁶-substituted or unsubstituted heteroaryl.

R⁶⁶ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁶⁷-substituted or unsubstituted alkyl, R⁶⁷-substituted or unsubstitutedheteroalkyl, R⁶⁷-substituted or unsubstituted cycloalkyl,R⁶⁷-substituted or unsubstituted heterocycloalkyl, R⁶⁷-substituted orunsubstituted aryl, or R⁶⁷-substituted or unsubstituted heteroaryl.

In embodiments, L⁷ is independently a bond, —N(R¹⁷)-L¹³-L¹⁴-,—N(R¹⁷)C(O)O-L¹³-L¹⁴-, —O-L¹³-L¹⁴-, —S-L¹³-L¹⁴-, —OC(O)-L¹³-L¹⁴-,—OC(O)N(R¹⁷)-L¹³-L¹⁴-, —OC(O)O-L¹³-L¹⁴-, —OSO₂-L¹³-L¹⁴-,—C(O)N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)-L¹³-L¹⁴-, —S(O)₂N(R¹⁷)-L¹³-L¹⁴-,—N(R¹⁷)S(O)₂-L¹³-L¹⁴-, R⁶⁸-substituted or unsubstituted alkylene,R⁶⁸-substituted or unsubstituted heteroalkylene, R⁶⁸-substituted orunsubstituted cycloalkylene, R⁶⁸ substituted or unsubstitutedheterocycloalkylene, R⁶⁸-substituted or unsubstituted arylene, orR⁶⁸-substituted or unsubstituted heteroarylene. L⁷ may be a bond. L⁷ maybe —N(R¹⁷⁷)-L¹³⁷-L¹⁴⁷-. L⁷ may be —N(R¹⁷⁷)C(O)O-L¹³⁷-L¹⁴⁷-. L⁷ may be—O-L¹³⁷-L¹⁴⁷-. L⁷ may be —S-L¹³⁷-L¹⁴⁷-. L⁷ may be —OC(O)-L¹³⁷-L¹⁴⁷-. L⁷may be —OC(O)N(R¹⁷⁷)-L¹³7-L¹⁴⁷-. L⁷ may be —OC(O)O-L¹³⁷-L¹⁴⁷-. L⁷ may be—OSO₂-L¹³⁷-L¹⁴⁷-. L⁷ may be —C(O)N(R¹⁷⁷)-L¹³⁷-L¹⁴⁷-. L⁷ may be—N(R¹⁷⁷)C(O)-L¹³⁷-L¹⁴⁷-. L⁷ may be —S(O)₂N(R¹⁷⁷)-L¹³⁷-L¹⁴⁷-. L⁷ may be—N(R¹⁷⁷)S(O)₂-L¹³⁷-L¹⁴⁷-. L⁷ may be —C(O)O-L¹³⁷-L¹⁴⁷-. L⁷ may be—SO₂-L¹³⁷-L¹⁴⁷-. L⁷ may be —N(H)—. L⁷ may be —N(H)C(O)O—. L⁷ may be —O—.L⁷ may be —S—. L⁷ may be —OC(O)—. L⁷ may be —OC(O)N(H)—. L⁷ may be—OC(O)O—. L⁷ may be —OSO₂—. L⁷ may be —C(O)N(H)—. L⁷ may be —N(H)C(O)—.L⁷ may be —S(O)₂N(H)—. L⁷ may be —N(H)S(O)₂—. L⁷ may be —C(O)O—. L⁷ maybe —SO₂—.

R⁶⁸ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁶⁹-substituted or unsubstituted alkyl, R⁶⁹-substituted or unsubstitutedheteroalkyl, R⁶⁹-substituted or unsubstituted cycloalkyl,R⁶⁹-substituted or unsubstituted heterocycloalkyl, R⁶⁹-substituted orunsubstituted aryl, or R⁶⁹-substituted or unsubstituted heteroaryl.

R⁶⁹ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁷⁰-substituted or unsubstituted alkyl, R⁷⁰-substituted or unsubstitutedheteroalkyl, R⁷⁰-substituted or unsubstituted cycloalkyl,R⁷⁰-substituted or unsubstituted heterocycloalkyl, R⁷⁰-substituted orunsubstituted aryl, or R⁷⁰-substituted or unsubstituted heteroaryl.

In embodiments, L¹¹ is independently a bond, —N(R¹⁷)-L¹³-L¹⁴-,—N(R¹⁷)C(O)O-L¹³-L¹⁴-, —O-L¹³-L¹⁴-, —S-L¹³-L¹⁴-, —OC(O)-L¹³-L¹⁴-,—OC(O)N(R¹⁷)-L¹³-L¹⁴-, —OC(O)O-L¹³-L¹⁴-, —OSO₂-L¹³-L¹⁴-,—C(O)N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)-L¹³-L¹⁴-, —S(O)₂N(R¹⁷)-L¹³-L¹⁴-,—N(R¹⁷)S(O)₂-L¹³-L¹⁴-, R⁷¹-substituted or unsubstituted alkylene,R⁷¹-substituted or unsubstituted heteroalkylene, R⁷¹-substituted orunsubstituted cycloalkylene, R⁷¹⁻substituted or unsubstitutedheterocycloalkylene, R⁷¹-substituted or unsubstituted arylene, orR⁷¹-substituted or unsubstituted heteroarylene. L¹¹ may be a bond. L¹¹may be —N(R¹⁷¹¹)-L¹³¹¹-L¹⁴¹¹-. L¹¹ may be —N(R¹⁷¹)C(O)O-L¹³¹¹-L¹⁴¹¹-.L¹¹ may be —O-L¹³¹¹-L¹⁴¹¹-. L¹¹ may be —S-L¹³¹¹-L¹⁴¹¹-. L¹¹ may be—OC(O)-L¹³¹¹-L¹⁴¹¹-. L¹¹ may be —OC(O)N(R¹⁷¹¹)-L¹³¹-L¹⁴¹¹-. L¹¹ may be—OC(O)O-L¹³¹¹-L¹⁴¹¹-. L¹¹ may be —OSO₂-L¹³¹¹-L¹⁴¹¹-. L¹¹ may be—C(O)N(R¹⁷¹¹)-L¹³¹¹-L¹⁴¹¹-. L¹¹ may be —N(R¹⁷¹¹)C(O)-L¹³¹¹-L¹⁴¹¹-. L¹¹may be —S(O)₂N(R¹⁷¹¹)-L¹³¹¹-L¹⁴¹¹-. L¹¹ may be—N(R¹⁷¹¹)S(O)₂-L¹³¹¹-L¹⁴¹¹-. L¹¹ may be —C(O)O-L¹³¹¹-L¹⁴¹¹-. L¹¹ may be—SO₂-L¹³¹¹-L¹⁴¹¹-. L¹¹ may be —N(H)—. L¹¹ may be —N(H)C(O)O—. L¹¹ may be—O—. L¹¹ may be —S—. L¹¹ may be —OC(O)—. L¹¹ may be —OC(O)N(H)—. L¹¹ maybe —OC(O)O—. L¹¹ may be —OSO₂—. L¹¹ may be —C(O)N(H)—. L¹¹ may be—N(H)C(O)—. L¹¹ may be —S(O)₂N(H)—. L¹¹ may be —N(H)S(O)₂—. L¹¹ may be—C(O)O—. L¹¹ may be —SO₂—.

R⁷¹ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁷²-substituted or unsubstituted alkyl, R⁷²-substituted or unsubstitutedheteroalkyl, R⁷²-substituted or unsubstituted cycloalkyl,R⁷²-substituted or unsubstituted heterocycloalkyl, R⁷²-substituted orunsubstituted aryl, or R⁷²-substituted or unsubstituted heteroaryl.

R⁷² is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁷³-substituted or unsubstituted alkyl, R⁷³-substituted or unsubstitutedheteroalkyl, R⁷³-substituted or unsubstituted cycloalkyl,R⁷³-substituted or unsubstituted heterocycloalkyl, R⁷³-substituted orunsubstituted aryl, or R⁷³-substituted or unsubstituted heteroaryl.

In embodiments, L¹² is independently a bond, —N(R¹⁷)-L¹³-L¹⁴-,—N(R¹⁷)C(O)O-L¹³-L¹⁴-, —O-L¹³-L¹⁴-, —S-L¹³-L¹⁴-, —OC(O)-L¹³-L¹⁴-,—OC(O)N(R¹⁷)-L¹³-L¹⁴-, —OC(O)O-L¹³-L¹⁴-, —OSO₂-L¹³-L¹⁴-,—C(O)N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)-L¹³-L¹⁴-, —S(O)₂N(R¹⁷)-L¹³-L¹⁴-,—N(R¹⁷)S(O)₂-L¹³-L¹⁴-, R⁷⁴-substituted or unsubstituted alkylene,R⁷⁴-substituted or unsubstituted heteroalkylene, R⁷⁴-substituted orunsubstituted cycloalkylene, R⁷⁴-substituted or unsubstitutedheterocycloalkylene, R⁷⁴-substituted or unsubstituted arylene, orR⁷⁴⁻substituted or unsubstituted heteroarylene. L¹² may be a bond. L¹²may be —N(R¹⁷¹²)-L¹³¹²-L¹⁴¹²-. L¹² may be —N(R¹⁷¹²)C(O)O-L¹³¹²-L¹⁴¹².L¹² may be —O-L¹³¹²-L¹⁴¹²-. L¹² may be —S-L¹³¹²-L¹⁴¹²-. L¹² may be—OC(O)-L¹³¹²-L¹⁴¹²-. L¹² may be —OC(O)N(R¹⁷¹²)-L¹³¹²-L¹⁴¹²-. L¹² may be—OC(O)O-L¹³¹²-L¹⁴¹²-. L¹² may be —OSO₂-L¹³¹²-L¹⁴¹²-. L¹² may be—C(O)N(R¹⁷¹²)-L¹³¹²-L¹⁴¹²-. L¹² may be —N(R¹⁷¹²)C(O)-L¹³¹²-L¹⁴¹²-. L¹²may be —S(O)₂N(R¹⁷¹²)-L¹³¹²-L¹⁴¹²-. L¹² may be—N(R¹⁷¹²)S(O)₂-L¹³¹²-L¹⁴¹²-. L¹² may be —C(O)O-L¹³¹²-L¹⁴¹²-. L¹² may be—SO₂-L¹³¹-L¹⁴¹²-. L¹² may be —N(H)—. L¹² may be —N(H)C(O)O—. L¹² may be—O—. L¹² may be —S—. L¹² may be —OC(O)—. L¹² may be —OC(O)N(H)—. L¹² maybe —OC(O)O—. L¹² may be —OSO₂—. L¹² may be —C(O)N(H)—. L¹² may be—N(H)C(O)—. L¹² may be —S(O)₂N(H)—. L¹² may be —N(H)S(O)₂—. L¹² may be—C(O)O—. L¹² may be —SO₂—.

R⁷⁴ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁷⁵-substituted or unsubstituted alkyl, R⁷⁵-substituted or unsubstitutedheteroalkyl, R⁷⁵-substituted or unsubstituted cycloalkyl,R⁷⁵-substituted or unsubstituted heterocycloalkyl, R⁷⁵-substituted orunsubstituted aryl, or R⁷⁵-substituted or unsubstituted heteroaryl.

R⁷⁵ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁷⁶-substituted or unsubstituted alkyl, R⁷⁶-substituted or unsubstitutedheteroalkyl, R⁷⁶-substituted or unsubstituted cycloalkyl,R⁷⁶-substituted or unsubstituted heterocycloalkyl, R⁷⁶-substituted orunsubstituted aryl, or R⁷⁶-substituted or unsubstituted heteroaryl.

In embodiments, L¹³ is independently a bond, —N(R¹⁷)—, —N(R¹⁷)C(O)O—,—O—, —S—, —OC(O)—, —OC(O)N(R¹⁷)—, —OC(O)O—, —OSO₂—, —C(O)N(R¹⁷)—,—N(R¹⁷)C(O)—, —S(O)₂N(R¹⁷)—, —N(R¹⁷)S(O)₂—, R⁷⁷-substituted orunsubstituted alkylene, R⁷⁷-substituted or unsubstituted heteroalkylene,R⁷⁷-substituted or unsubstituted cycloalkylene, R⁷⁷-substituted orunsubstituted heterocycloalkylene, R⁷⁷-substituted or unsubstitutedarylene, or R⁷⁷ substituted or unsubstituted heteroarylene. L¹³ may be abond. L¹³ may be —N(H)—. L¹³ may be —N(H)C(O)O—. L¹³ may be —O—. L¹³ maybe —S—. L¹³ may be —OC(O)—. L¹³ may be —OC(O)N(H)—. L¹³ may be —OC(O)O—.L¹³ may be —OSO₂—. L¹³ may be —C(O)N(H)—. L¹³ may be —N(H)C(O)—. L¹³ maybe —S(O)₂N(H)—. L¹³ may be —N(H)S(O)₂—. L¹³ may be —C(O)O—. L¹³ may be—SO₂—.

R⁷⁷ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁷⁸-substituted or unsubstituted alkyl, R⁷⁸-substituted or unsubstitutedheteroalkyl, R⁷⁸-substituted or unsubstituted cycloalkyl,R⁷⁸-substituted or unsubstituted heterocycloalkyl, R⁷⁸-substituted orunsubstituted aryl, or R⁷⁸-substituted or unsubstituted heteroaryl.

R⁷⁸ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁷⁹-substituted or unsubstituted alkyl, R⁷⁹-substituted or unsubstitutedheteroalkyl, R⁷⁹-substituted or unsubstituted cycloalkyl,R⁷⁹-substituted or unsubstituted heterocycloalkyl, R⁷⁹-substituted orunsubstituted aryl, or R⁷⁹-substituted or unsubstituted heteroaryl.

In embodiments, L¹⁴ is independently a bond, —N(R¹⁷)—, —N(R¹⁷)C(O)O—,—O—, —S—, —OC(O)—, —OC(O)N(R¹⁷)—, —OC(O)O—, —OSO₂—, —C(O)N(R¹⁷)—,—N(R¹⁷)C(O)—, —S(O)₂N(R¹⁷)—, —N(R¹⁷)S(O)₂—, R⁸⁰-substituted orunsubstituted alkylene, R⁸⁰-substituted or unsubstituted heteroalkylene,R⁵⁰-substituted or unsubstituted cycloalkylene, R⁸⁰-substituted orunsubstituted heterocycloalkylene, R⁵⁰-substituted or unsubstitutedarylene, or R⁸⁰-substituted or unsubstituted heteroarylene. L¹⁴ may be abond. L¹⁴ may be —N(H)—. L¹⁴ may be —N(H)C(O)O—. L¹⁴ may be —O—. L¹⁴ maybe —S—. L¹⁴ may be —OC(O)—. L¹⁴ may be —OC(O)N(H)—. L¹⁴ may be —OC(O)O—.L¹⁴ may be —OSO₂—. L¹⁴ may be —C(O)N(H)—. L¹⁴ may be —N(H)C(O)—. L¹⁴ maybe —S(O)₂N(H)—. L¹⁴ may be —N(H)S(O)₂—. L¹⁴ may be —C(O)O—. L¹⁴ may be—SO₂—.

R⁸⁰ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁸¹-substituted or unsubstituted alkyl, R⁸¹-substituted or unsubstitutedheteroalkyl, R⁸¹-substituted or unsubstituted cycloalkyl,R⁸¹-substituted or unsubstituted heterocycloalkyl, R⁸¹-substituted orunsubstituted aryl, or R⁸¹-substituted or unsubstituted heteroaryl.

R⁸¹ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁸²-substituted or unsubstituted alkyl, R⁸²-substituted or unsubstitutedheteroalkyl, R⁸²-substituted or unsubstituted cycloalkyl,R⁸²-substituted or unsubstituted heterocycloalkyl, R⁸²-substituted orunsubstituted aryl, or R⁸²-substituted or unsubstituted heteroaryl.

R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵, R⁵⁸, R⁶¹, R⁶⁴, R⁶⁷,R⁷⁰, R⁷³, R⁷⁶, R⁷⁹, and R⁸², are independently hydrogen, oxo, halogen,—CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, unsubstituted alkyl, unsubstitutedheteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,unsubstituted aryl, or unsubstituted heteroaryl.

In embodiments, the compound is in a pharmaceutically acceptable salt.In embodiments, the compound is not in a pharmaceutically acceptablesalt. In embodiments, the compound is co-administered with a secondagent (e.g. therapeutic agent). In embodiments, the second agent isadministered in a therapeutically effective amount. In embodiments, thesecond agent is an agent for treating an infectious disease. Inembodiments, the second agent is an agent for treating a parasiticdisease. In embodiments, the second agent is an agent for treatingmalaria. In embodiments, the second agent is an agent for treatingcancer. In embodiments, the second agent is an agent for treating solidtumors. In embodiments, the second agent is an agent for treatinghematological cancers. In embodiments, the second agent is an agent fortreating diseases characterized by an increased level of iron relativeto a control (e.g. subject without the disease or sample from a subjectwithout the disease). In embodiments, the second agent is an agent fortreating diseases characterized by an increased level of a reductant(e.g. biological reductant, iron) relative to a control (e.g. subjectwithout the disease or sample from a subject without the disease).

Non-limiting examples of prodrug formulae described herein are shownbelow, wherein (-X-AGENT) represent R groups as described herein (e.g.R⁴, R⁵, R⁶, R⁷, R¹¹, or R¹²). In embodiments, each (-X-AGENT) isindependently a drug moiety, detectable moiety, or protein moiety. Inembodiments, the compound is a compound described herein or a compoundhaving the formula of a compound described herein, including in theexamples section below and in the tables contained therein, for example

or another compound or formula described herein.

An example mechanism of drug delivery via reaction of a prodrug (e.g. asdescribed herein) with ferrous iron:

C. Pharmaceutical Compositions

In an aspect is provided a pharmaceutical composition including apharmaceutically acceptable excipient and a compound described herein(including in an aspect, embodiment, table, example, or claim), or apharmaceutically acceptable salt thereof.

In embodiments of the pharmaceutical compositions, the pharmaceuticalcomposition includes a compound, or pharmaceutically acceptable saltthereof, as described herein (e.g. compound of formula I, or anyembodiment thereof) in a therapeutically effective amount. Inembodiments of the pharmaceutical compositions, the pharmaceuticalcomposition includes a second agent (e.g. therapeutic agent). Inembodiments of the pharmaceutical compositions, the pharmaceuticalcomposition includes a second agent in a therapeutically effectiveamount. In embodiments of the pharmaceutical compositions, the secondagent is an agent for treating cancer. In embodiments, the second agentis an agent for treating an infectious disease. In embodiments, thesecond agent is an agent for treating a bacterial disease. Inembodiments, the second agent is an agent for treating a parasiticdisease. In embodiments, the second agent is an agent for treatingmalaria. In embodiments, the second agent is an anti-cancer agent. Inembodiments, the second agent is an anti-infective agent. Inembodiments, the second agent is an anti-parasitic agent. Inembodiments, the second agent is an anti-malarial agent. In embodiments,the second agent is an agent for treating solid tumors. In embodiments,the second agent is an agent for treating hematological cancers. Inembodiments, the second agent is an agent for treating diseasescharacterized by an increased level of iron relative to a control (e.g.subject without the disease or sample from a subject without thedisease). In embodiments, the second agent is an agent for treatingdiseases characterized by an increased level of reductant (e.g.biological reductant, Fe^(II)) relative to a control (e.g. subjectwithout the disease or sample from a subject without the disease).

D. Methods

In an aspect is provided a method of treating a disease in a patient inneed of such treatment, said method including administering atherapeutically effective amount of a compound described herein(including in an aspect, embodiment, table, example, or claim), or apharmaceutically acceptable salt thereof, to the patient.

In an aspect is provided a compound as described herein (including in anaspect, embodiment, table, example, or claim), or a pharmaceuticallyacceptable salt thereof, for use in the treatment of a disease in asubject. The use may include administering to the subject a compounddescribed herein. The use may include administering to the subject atherapeutically effective amount of a compound described herein. In anaspect is provided a pharmaceutical composition as described herein(including in an aspect, embodiment, table, example, or claim) for usein the treatment of a disease in a subject.

In an aspect is provided a compound as described herein for use in themanufacture of a medicament for treatment of a disease. In an aspect isprovided a pharmaceutical composition as described herein for use in themanufacture of a medicament for treatment of a disease.

In embodiments, the disease is associated with a cell or organism havingan increased level of a reductant (e.g. biological reductant, Fe^(II))compared to a standard control (e.g. subject without the disease orsample from a subject without the disease). In embodiments, the diseaseis associated with a cell or organism having an increased Fe^(II) levelcompared to a standard control (e.g. subject without the disease orsample from a subject without the disease). In some embodiments, themethod of treating is a method of preventing.

Drug moieties that form part of the prodrugs described herein obtainfunctionality due to chemical changes in the prodrugs that occur underphysiological conditions. For example, the trioxane or trioxolane ringmoiety of prodrugs described herein (i.e. compounds described herein)may react with Fe^(II), leading to the formation of a ketone species.The ketone then undergoes a beta-elimination reaction to release theagent (e.g. drug, detectable agent, protein, sideropohore, antibody) anda new ketone containing compound. The agent (e.g. drug, detectableagent, protein, sideropohore, antibody) obtained from the prodrug due tochemical changes under physiological conditions may be capable of use intreating or detecting mammalian disease caused by a cell or organismhaving increased reductant (e.g. biological reductant, Fe^(II)) levelscompared to reductant (e.g. biological reductant, Fe^(II)) levels inmammalian plasma. The agent (e.g. drug, detectable agent, protein,sideropohore, antibody) obtained from the prodrug due to chemicalchanges under physiological conditions may be capable of use in treatingor detecting mammalian disease caused by a cell or organism havingincreased Fe^(II) levels compared to Fe^(II) levels in mammalian plasma.The mammalian disease may be a human disease. In some embodiments, thehuman disease may be a parasitic disease or a cancer. In embodiments,the disease may be malaria, schistosomiasis, trypanosomiasis, leukemia,cervical cancer, breast cancer, colon cancer, ovarian cancer, prostatecancer, thyroid cancer, lung cancer, glioblastoma, or melanoma. Inembodiments, the disease may be a cancer where transferrin receptors(CD71) are over-expressed as compared to normal cells. In embodiments,the disease may be a bacterial disease. In embodiments, the disease maybe an infectious disease.

In another aspect of the present invention, the prodrug compounds(compound described herein, including formula I and embodiments) can beemployed in methods to treat a disease that is associated with a cell ororganism that has increased reducant (e.g. biological reducant, Fe^(II))levels compared to reducant (e.g. biological reducant, Fe^(II)) levelsin the same location in a mammal without the disease (e.g. in mammalianplasma).

In an aspect is provided a compound as described herein (including in anaspect, embodiment, table, example, or claim), or a pharmaceuticallyacceptable salt thereof, for use in the treatment of a disease that isassociated with a cell or organism that has increased reducant (e.g.biological reducant, Fe^(II)) levels compared to reducant (e.g.biological reducant, Fe^(II)) levels in the same location in a mammalwithout the disease (e.g. in mammalian plasma). The use may includeadministering to the subject a compound described herein. The use mayinclude administering to the subject a therapeutically effective amountof a compound described herein. In an aspect is provided apharmaceutical composition as described herein (including in an aspect,embodiment, table, example, or claim) for use in the treatment of adisease that is associated with a cell or organism that has increasedreducant (e.g. biological reducant, Fe^(II)) levels compared to reducant(e.g. biological reducant, Fe^(II)) levels in the same location in amammal without the disease (e.g. in mammalian plasma).

In an aspect is provided a compound as described herein for use in themanufacture of a medicament for treatment of a disease that isassociated with a cell or organism that has increased reducant (e.g.biological reducant, Fe^(II)) levels compared to reducant (e.g.biological reducant, Fe^(II)) levels in the same location in a mammalwithout the disease (e.g. in mammalian plasma). In an aspect is provideda pharmaceutical composition as described herein for use in themanufacture of a medicament for treatment of a disease that isassociated with a cell or organism that has increased reducant (e.g.biological reducant, Fe^(II)) levels compared to reducant (e.g.biological reducant, Fe^(II)) levels in the same location in a mammalwithout the disease (e.g. in mammalian plasma).

The method or use may include administering an effective amount of theprodrug compound (or pharmaceutical formulation thereof) to a patient inneed of such treatment. Increased reducant (e.g. biological reducant,Fe^(II)) levels are levels (e.g. cellular) of reducant (e.g. biologicalreducant, Fe^(II)) that are sufficiently high to cause disease in apatient and/or are higher than in the plasma of a patient. In someembodiments, the method or use includes administering an effectiveamount of a prodrug compound and a reducant (e.g. biological reducant,Fe^(II)) containing agent to a patient in need of such treatment. Thereducant (e.g. biological reducant, Fe^(II)) containing agent may beco-administered with the prodrug (compound described herein, includingformula I and embodiments). In another embodiment the reducant (e.g.biological reducant, Fe^(II)) containing agent may be administeredbefore or after prodrug administration. A disease that is associatedwith a cell or organism that has increased reducant (e.g. biologicalreducant, Fe^(II)) levels refers to a disease in which reducant (e.g.biological reducant, Fe^(II)) levels are elevated relative to reducant(e.g. biological reducant, Fe^(II))^(I) levels in the cell or organismin the absence of the disease. The disease associated with increasedreducant (e.g. biological reducant, Fe^(II)) levels is not bound by anyparticular mechanistic theory, and include those diseases resulting inincreased reducant (e.g. biological reducant, Fe^(II)) levels and/orcaused by increased reducant (e.g. biological reducant, Fe^(II)) levels.Thus, in some embodiments, the increased reducant (e.g. biologicalreducant, Fe^(II)) levels are the result of the disease. In someembodiments, the increased reducant (e.g. biological reducant, Fe^(II))levels are the result of the disease, and additionally the increasedreducant (e.g. biological reducant, Fe^(II)) levels may cause symptomsrelated to increased reducant (e.g. biological reducant, Fe^(II))levels.

In another aspect of the present invention, the prodrug compounds(compound described herein, including formula I and embodiments) can beemployed in methods to treat a disease that is associated with a cell ororganism that has increased Fe^(II) levels compared to Fe^(II) levels inmammalian plasma.

In an aspect is provided a compound as described herein (including in anaspect, embodiment, table, example, or claim), or a pharmaceuticallyacceptable salt thereof, for use in the treatment of a disease that isassociated with a cell or organism that has increased Fe^(II) levelscompared to Fe^(II) levels in mammalian plasma. The use may includeadministering to the subject a compound described herein. The use mayinclude administering to the subject a therapeutically effective amountof a compound described herein. In an aspect is provided apharmaceutical composition as described herein (including in an aspect,embodiment, table, example, or claim) for use in the treatment of adisease that is associated with a cell or organism that has increasedFe^(II) levels compared to Fe^(II) levels in mammalian plasma.

In an aspect is provided a compound as described herein for use in themanufacture of a medicament for treatment of a disease that isassociated with a cell or organism that has increased Fe^(II) levelscompared to Fe^(II) levels in mammalian plasma. In an aspect is provideda pharmaceutical composition as described herein for use in themanufacture of a medicament for treatment of a disease that isassociated with a cell or organism that has increased Fe^(II) levelscompared to Fe^(II) levels in mammalian plasma.

The method or use may include administering an effective amount of theprodrug compound (or pharmaceutical formulation thereof) to a patient inneed of such treatment. Increased Fe^(II) levels are cellular levels ofFe^(II) that are sufficiently high to cause disease in a patient and arehigher than in the plasma of a patient. In some embodiments, the methodor use includes administering an effective amount of a prodrug compoundand an Fe^(II) containing agent to a patient in need of such treatment.In another embodiment, the Fe^(II) containing agent is ferroglycinesulfate or transferrin. The Fe^(II) containing agent may beco-administered with the prodrug (compound described herein, includingformula I and embodiments). In another embodiment the Fe^(II) containingagent may be administered before or after prodrug administration. Adisease that is associated with a cell or organism that has increasedFe^(II) levels compared to Fe^(II) levels in mammalian plasma refers toa disease in which Fe^(II) levels are elevated relative to Fe^(II)levels in mammalian plasma in the absence of the disease. The diseaseassociated with increased Fe^(II) levels is not bound by any particularmechanistic theory, and include those diseases resulting in increaseFe^(II) levels and/or caused by Fe^(II) levels. Thus, in someembodiments, the increased Fe^(II) levels are the result of the disease.In some embodiments, the increased Fe^(II) levels are the result of thedisease, and additionally the increased Fe^(II) levels cause symptomsrelated to increased Fe^(II) levels.

In an aspect is provided a method of identifying a patient having adisease associated with a cell or organism having an increased reducant(e.g. biological reducant, Fe^(II)) level compared to a standardcontrol, the method including administering an effective amount of acompound described herein (including in an aspect, embodiment, table,example, or claim), or a pharmaceutically acceptable salt thereof, tothe patient. The method may include detecting the presence of thecompound. The method may include detecting an increased level of thecompound or detectable agent compared to the level of compound ordetectable agent detected in a patient without the disease.

In an aspect is provided a compound as described herein (including in anaspect, embodiment, table, example, or claim), or a pharmaceuticallyacceptable salt thereof, for use in identifying a patient having adisease associated with a cell or organism having an increased reducant(e.g. biological reducant, Fe^(II)) level compared to a standardcontrol. The use may include administering to the subject a compounddescribed herein. The use may include administering to the subject aneffective amount of a compound described herein.

In an aspect is provided a method of identifying a patient having adisease associated with a cell or organism having an increased Fe^(II)level compared to a standard control, the method including administeringan effective amount of a compound described herein (including in anaspect, embodiment, table, example, or claim), or a pharmaceuticallyacceptable salt thereof, to the patient.

In an aspect is provided a compound as described herein (including in anaspect, embodiment, table, example, or claim), or a pharmaceuticallyacceptable salt thereof, for use in identifying a patient having adisease associated with a cell or organism having an increased Fe^(II)level compared to a standard control. The use may include administeringto the subject a compound described herein. The use may includeadministering to the subject an effective amount of a compound describedherein.

The method or use may include detecting the presence of the compound.The method or use may include detecting an increased level of thecompound or detectable agent compared to the level of compound ordetectable agent detected in a patient without the disease.

In embodiments, the compound includes a detectable moiety. Inembodiments, the detectable moiety is a fluorescent moiety. Inembodiments, the detectable moiety is a moiety of a fluorescent dye,electron-dense reagent, enzyme (e.g., as commonly used in an ELISA),biotin, digoxigenin, paramagnetic molecule, paramagnetic nanoparticle,ultrasmall superparamagnetic iron oxide (“USPIO”) nanoparticle, USPIOnanoparticle aggregate, nanoparticle contrast agent, liposome or otherdelivery vehicle containing Gadolinium chelate (“Gd-chelate”) molecules,Gadolinium, radioisotope (e.g. ³²P), radionuclide (e.g. carbon-11,nitrogen-13, oxygen-15, fluorine-18, rubidium-82), fluorodeoxyglucose(e.g. fluorine-18 labeled), gamma ray emitting radionuclide,positron-emitting radionuclide, iodinated contrast agent (e.g. iohexol,iodixanol, ioversol, iopamidol, ioxilan, iopromide, diatrizoate,metrizoate, ioxaglate), barium sulfate, thorium dioxide, gold, goldnanoparticle, gold nanoparticle aggregate, fluorophore, two-photonfluorophore, fluorescent protein, xanthene derivative (e.g. fluorescein,rhodamine, Oregon green, eosin, or Texas red), cyanine or derivative(e.g. cyanine, indocarbocyanine, oxacarbocyanine, thiacarbocyanine ormerocyanine), napththalene derivative (e.g. dansyl or prodanderivative), coumarin or a derivative, oxadiazole derivative (e.g.pyridyloxazole, nitrobenzoxadiazole or benzoxadiazole), anthracenederivative (e.g. anthraquinone, DRAQ5, DRAQ7, or CyTRAK Orange), pyrenederivative (e.g. cascade blue or derivative), oxazine derivative (e.g.Nile red, Nile blue, cresyl violet, oxazine 170), acridine derivative(e.g. proflavin, acridine orange, acridine yellow), arylmethinederivative (e.g. auramine, crystal violet, malachite green),tetrapyrrole derivative (e.g. porphin, phthalocyanine, bilirubin), CFDye™, DRAQ™, CyTRAK™, BODIPY™, Alexa Fluor™, DyLight Fluor™, Atto™,Tracy™, FluoProbe™, Abberior Dve™. DY™ dyes, MegaStokes Dye™, Sulfo Cy™,Seta™ dyes, SeTau™ dye, Square Dye™, Quasar™ dyes, Cal Fluor™ dyes,SureLight Dye™, PerCP™, Phycobilisome™, APC™, APCXL™, RPE™, or BPE™.

In another aspect, is provided a method of detecting a detectable agent(e.g. fluorescent agent) in an organism, by administering a compounddescribed herein to an organism, allowing the organism to metabolize thecompound thereby producing a detectable agent (e.g fluorescent agent),and detecting the detectable agent (e.g. fluorescent agent) in a samplefrom the organism.

In another aspect, the present invention provides a method of detectinga detectable agent (e.g. fluorescent agent) in a sample from anorganism, by administering a compound described herein to the samplefrom an organism, allowing the sample to metabolize the compound therebyproducing a detectable agent (e.g fluorescent agent), and detecting thedetectable agent (e.g. fluorescent agent) in the sample.

E. Additional Embodiments

1. A compound having the formula:

wherein L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, L⁹, L¹¹, and L¹² are independently abond, —N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)O-L¹³-L¹⁴-, —O-L¹³-L¹⁴-, —S-L¹³-L¹⁴-,—OC(O)-L¹³-L¹⁴-, —OC(O)N(R¹⁷)-L¹³-L¹⁴-, —OC(O)O-L¹³-L¹⁴-,—OSO₂-L¹³-L¹⁴-, —C(O)N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)-L¹³-L¹⁴-,—S(O)₂N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)S(O)₂-L¹³-L¹⁴-, substituted orunsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene; L¹⁰ is —N(-L¹¹-R¹¹)— or—C((-L¹¹-R¹¹)(-L¹²-R¹²))—; each L¹³ and L¹⁴ are independently selectedfrom a bond, —N(R¹⁷)—, —N(R¹⁷)C(O)O—, —O—, —S—, —OC(O)—, —OC(O)N(R¹⁷)—,—OC(O)O—, —OSO₂—, —C(O)N(R¹⁷)—, —N(R¹⁷)C(O)—, —S(O)₂N(R¹⁷)—,—N(R¹⁷)S(O)₂—, substituted or unsubstituted alkylene, substituted orunsubstituted heteroalkylene, substituted or unsubstitutedcycloalkylene, substituted or unsubstituted heterocycloalkylene,substituted or unsubstituted arylene, or substituted or unsubstitutedheteroarylene; R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹, and R¹², areindependently hydrogen, oxo, halogen, —CX₃, —CN, —SO₂Cl, —SO_(n)R¹⁶,—SO_(v)NR¹³R¹⁴, —NHNH₂, —ONR¹³R¹⁴, —NHC═(O)NHNH₂, —NHC═(O)NR¹³R¹⁴,—N(O)_(m), —NR¹³R¹⁴, —C(O)R¹⁵, —C(O)—OR¹⁵, —C(O)NR¹³R¹⁴, —OR¹⁶,—NR¹³SO₂R¹⁶, —NR¹³C═(O)R¹⁵, —NR¹³C(O)—OR¹⁵, —NR¹³OR¹⁵, —OCX₃, —OCHX₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, a protein moiety, a detectablemoiety, or a drug moiety; R⁵ and R¹¹ substituents may be joined to forma substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁶ and R¹¹ substituents may be joined to forma substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R² and R³, R⁴ and R⁵, R⁶ and R⁷, R⁸ and R⁹, orR¹¹ and R¹² may be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; eachR¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are independently hydrogen, halogen, —CF₃,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹³and R¹⁴ substituents bonded to the same atom may be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl; R¹⁸ and R¹⁹ are independently hydrogen,halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, a protein moiety, detectable moiety,siderophore moiety, or a drug moiety; R¹⁸ and R¹⁹ may be joined to forma substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, protein moiety, detectable moiety, siderophore moiety,or drug moiety; m and v are independently 1 or 2; n is independently aninteger from 0 to 2; Y is —O—, —S—, —OO—, —CH₂O—, or —OCH₂—; and X isindependently —Cl, —Br, —I, or —F.

2. The compound of embodiment 1, wherein the compound is not a compoundwherein R¹¹ and R¹² do not comprise a drug moiety, protein moiety, ordetectable moiety; L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, and L⁹ are bonds; and R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are hydrogen.

3. The compound of embodiment 1, wherein the compound is not a compoundwherein R¹¹ and R¹² do not comprise a drug moiety, protein moiety, ordetectable moiety; R¹⁸ and R¹⁹ are joined to form a substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,protein moiety, detectable moiety, or drug moiety; L², L³, L⁴, L⁵, L⁶,L⁷, L⁸, and L⁹ are bonds; and R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ arehydrogen.

4. The compound of embodiment 1, wherein the compound is not a compoundwherein: R¹¹ and R¹² do not comprise a drug moiety, protein moiety, ordetectable moiety; R¹⁸ and R¹⁹ are joined to form an unsubstitutedadamantyl; L², L³, L⁴, L⁵, L⁶, L⁷, L⁸, and L⁹ are bonds; and R², R³, R⁴,R⁵, R⁶, R⁷, R⁸, and R⁹ are hydrogen.

5. The compound of one of embodiments 1 to 4 having the formula:

wherein Ring A is a substituted or unsubstituted cycloalkylene orsubstituted or unsubstituted heterocycloalkylene; R¹ is hydrogen,halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, a protein moiety, a detectable moiety, asiderophore, moiety, or a drug moiety; L¹ is independently a bond,—N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)O-L¹³-L¹⁴-, —O-L¹³-L¹⁴-, —S-L¹³-L¹⁴-,—OC(O)-L¹³-L¹⁴-, —OC(O)N(R 17)-L¹³-L¹⁴-, —OC(O)O-L¹³-L¹⁴-,—OSO₂-L¹³-L¹⁴-, —C(O)N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)-L¹³-L¹⁴-,—S(O)₂N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)S(O)₂-L¹³-L¹⁴-, substituted orunsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene.

6. A compound of one of embodiments 1 to 5 having the formula:

7. The compound of one of embodiments 5 to 6, wherein -L¹-R¹ is —H.

8. The compound of one of embodiments 5 to 6, wherein -L¹ is

9. The compound of one of embodiments 5 to 6, wherein -L¹ is is—NHC(O)—(CH₂)_(W)—NHC(O)O—(CH₂)_(Y1)—,—NHC(O)—(CH₂)_(W)—C(O)NH—(CH₂)_(Y1)—, —NHC(O)—(CH₂) w-C(O)—,—NHC(O)—(CH₂)_(W)—NH—, —NHC(O)—(CH₂)_(W)—NHC(O)—,—NHC(O)—(CH₂)_(W)—C(O)NH—, —NHC(O)—(CH₂)_(W)—NHC(O)O—,—NHC(O)—(CH₂)_(W)—(OCH₂CH₂)_(T1)—C(O)NH—(CH₂)_(Y1)—,—NHC(O)—(CH₂)_(W)—(OCH₂CH₂)_(T1)—C(O)NH—(CH₂)_(Y1)—C(O)—; W is aninteger between 1 and 8; T1 is an integer between 1 and 8, and Y1 is aninteger between 1 and 8.

10. The compound of one of embodiments 5 to 6 or 8 to 9, wherein R¹ is aprotein moiety.

11. The compound of one of embodiments 5 to 6 or 8 to 9, wherein R¹ is asiderophore moiety.

12. The compound of embodiment 10, wherein R¹ is an antibody moiety.

13. The compound of one of embodiments 1 to 12, wherein L², L³, L⁴, L⁶,L⁷, L⁸, L⁹, L¹¹, and L¹² are a bond; R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹,and R¹² are hydrogen; L¹⁰ is —CH₂—; L⁵ is a bond, —N(R¹⁷)-L¹³-L¹⁴-,—N(R¹⁷)C(O)O-L¹³-L¹⁴-, —O-L¹³-L¹⁴-, —S-L¹³-L¹⁴-, —OC(O)-L¹³-L¹⁴-,—OC(O)N(R¹⁷)-L¹³-L¹⁴-, —OC(O)O-L¹³-L¹⁴-, —OSO₂-L¹³-L¹⁴-,—C(O)N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)-L¹³-L¹⁴-, —S(O)₂N(R¹⁷)-L¹³-L¹⁴-,—N(R¹⁷)S(O)₂-L¹³-L¹⁴-; and R⁵ is a protein moiety, drug moiety, or adetectable moiety.

14. The compound of embodiment 13, wherein L⁵ is a bond,—N(R¹⁷)-L¹³-L¹⁴-, —O-L¹³-L¹⁴-, —OC(O)-L¹³-L¹⁴-, or—OC(O)N(R¹⁷)-L¹³-L¹⁴-.

15. The compound of one of embodiments 1 to 12, wherein L², L³, L⁴, L⁶,L⁸, L⁹, L¹¹, and L¹² are a bond; R², R³, R⁵, R⁶, R⁸, R⁹, R¹¹, and R¹²are hydrogen; L⁵ and L⁷ are independently a bond, —N(R¹⁷)-L¹³-L¹⁴-,—N(R¹⁷)C(O)O-L¹³-L¹⁴-, —O-L¹³-L¹⁴-, —S-L¹³-L¹⁴-, —OC(O)-L¹³-L¹⁴-,—OC(O)N(R¹⁷)-L¹³-L¹⁴-, —OC(O)O-L¹³-L¹⁴-, —OSO₂-L¹³-L¹⁴-,—C(O)N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)-L¹³-L¹⁴-, —S(O)₂N(R¹⁷)-L¹³-L¹⁴-, or—N(R¹⁷)S(O)₂-L¹³-L¹⁴-; and R⁵ and R⁷ are each independently a drugmoiety, protein moiety, or detectable moiety.

16. The compound of embodiment 15, wherein L⁵ and L⁷ are independently abond, —N(R⁷)-L¹³-L¹⁴-, —O-L¹³-L¹⁴-, —OC(O)-L¹³-L¹⁴-, or—OC(O)N(R¹⁷)-L¹³-L¹⁴-.

17. The compound of one of embodiments 1 to 12, wherein L², L³, L⁴, L⁵,L⁶, L⁷, L⁸, L⁹, and L¹² are a bond; R², R³, R⁴, R⁵, R⁶, R⁷, R, R⁹, andR¹² are hydrogen; L¹⁰ is —N(-L¹¹-R¹¹)—; L¹¹ is a bond, —N(R¹⁷)-L¹³-L¹⁴-,—N(R¹⁷)C(O)O-L¹³-L¹⁴-, —O-L¹³-L¹⁴-, —S-L¹³-L¹⁴-, —OC(O)-L¹³-L¹⁴-,—OC(O)N(R¹⁷)-L¹³-L¹⁴-, —OC(O)O-L¹³-L¹⁴-, —OSO₂-L¹³-L¹⁴-,—C(O)N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)-L¹³-L¹⁴-, —S(O)₂N(R¹⁷)-L¹³-L¹⁴-,—N(R¹⁷)S(O)₂-L¹³-L¹⁴-; and R¹ is a drug moiety, protein moiety, ordetectable moiety.

18. The compound of embodiment 17, wherein L¹ is independently a bond,—N(R⁷)-L¹³-L¹⁴-, —O-L¹³-L¹⁴-, —OC(O)-L¹³-L¹⁴-, or —OC(O)N(R¹⁷)-L¹³-L¹⁴-.

19. The compound of one of embodiments 17 to 18, wherein R¹¹ is anantibody moiety.

20. The compound of one of embodiments 1 to 12, wherein L², L³, L⁴, L⁶,L⁷, L⁸, L⁹, L¹, and L¹² are a bond; R², R³, R⁴, R⁶, R⁸, R⁹, and R¹² arehydrogen; L¹⁰ is —CH(—R¹¹)—; R⁷ and R¹ are joined to form a substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; L⁵ is a bond, —N(R¹⁷)-L¹³-L¹⁴-,—N(R¹⁷)C(O)O-L¹³-L¹⁴-, —O-L¹³-L¹⁴-, —S-L¹³-L¹⁴-, —OC(O)-L¹³-L¹⁴-,—OC(O)N(R 17)-L¹³-L¹⁴-, —OC(O)O-L¹³-L¹⁴-, —OSO₂-L¹³-L¹⁴-,—C(O)N(R¹⁷)-L¹³-L¹⁴-, —N(R¹⁷)C(O)-L¹³-L¹⁴-, —S(O)₂N(R¹⁷)-L¹³-L¹⁴-, or—N(R¹⁷)S(O)₂-L¹³-L¹⁴-; and R⁵ is a drug moiety, protein moiety, ordetectable moiety.

21. The compound of embodiment 20, wherein L⁵ is independently a bond,—N(R¹⁷)-L¹³-L¹⁴-, —O-L¹³-L¹⁴-, —OC(O)-L¹³-L¹⁴-, or—OC(O)N(R¹⁷)-L¹³-L¹⁴-.

22. The compound of embodiment 20, wherein R⁷ and R¹¹ are joined to forman unsubstituted aryl.

23. The compound of one of embodiments 1 to 22, wherein each L¹³ isindependently selected from a bond or substituted or unsubstitutedarylene.

24. The compound of embodiment 23, wherein each L¹³ is independentlyselected from a bond or substituted or unsubstituted phenylene.

25. The compound of one of embodiments 1 to 24, wherein each L¹⁴ isindependently selected from a bond, substituted or unsubstitutedalkylene, or substituted or unsubstituted heteroalkylene.

26. The compound of embodiment 25, wherein each L¹⁴ is independentlyselected from a bond, —(CH₂)_(w)—, or —(CH₂)_(w)—OC(O)—; w is an integerbetween 1 and 4.

27. The compound of one of embodiments 1 to 26, wherein each -L¹³-L¹⁴-is independently selected from a bond, -Ph-(CH₂)_(w)—, or-Ph-(CH₂)_(w)—OC(O)—; w is an integer between 1 and 4.

28. The compound of one of embodiments 1 to 27, wherein -L¹³-L¹⁴- is abond.

29. The compound of one of embodiments 1 to 27, wherein -L¹³-L¹⁴- is-Ph-(CH₂)_(w)—; w is an integer between 1 and 4.

30. The compound of one of embodiments 1 to 27, wherein -L¹³-L¹⁴- is-Ph-(CH₂)_(w)—OC(O)—; w is an integer between 1 and 4.

31. The compound of one of embodiments 26 to 30, wherein w is 1.

32. The compound of one of embodiments 1 to 31, wherein the drug moietyis independently a monovalent radical of an anti-infective agent.

33. The compound of embodiment 32, wherein the anti-infective agent isan anti-parasitic agent.

34. The compound of embodiment 32, wherein the anti-infective agent isan anti-malarial drug.

35. The compound of embodiment 32, wherein the anti-infective agent isan anti-bacterial drug.

36. The compound of one of embodiments 1 to 31, wherein the drug moietyis independently a monovalent radical of an anti-cancer drug.

37. The compound of one of embodiments 1 to 36, wherein the detectablemoiety is independently a monovalent radical of a fluorophore.

38. The compound of one of embodiments 1 to 37, wherein the proteinmoiety is independently a monovalent radical of an antibody.

39. A pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and a compound of one of embodiments 1 to 38.

40. A method of treating a disease in a patient in need of suchtreatment, said method comprising administering a therapeuticallyeffective amount of a compound of one of embodiments 1 to 38 to saidpatient.

41. The method of embodiment 40, wherein the disease is associated witha cell or organism having an increased Fe^(II) level compared to astandard control.

42. The method of embodiment 40, wherein the disease is cancer.

43. The method of embodiment 40, wherein the disease is a hematologicalcancer.

44. The method of embodiment 40, wherein the disease is anon-hematological cancer.

45. The method of embodiment 40, wherein the disease is malaria.

46. The method of embodiment 40, wherein the disease is a bacterialdisease.

47. The method of embodiment 40, wherein the disease is a parasiticdisease.

48. A method of identifying a patient having a disease associated with acell or organism having an increased Fe^(II) level compared to astandard control, said method comprising administering an effectiveamount of a compound of one of embodiments 1 to 38 to said patient.

49. A method of identifying a patient having a disease associated withan increased reductant level compared to a standard control, said methodcomprising obtaining a biological sample from said patient, contactingsaid biological sample with an effective amount of a compound of one ofembodiments 1 to 38, wherein said compound comprises a detectablemoiety, detecting an increased level of said detectable moiety or adetectable agent resulting from cleavage of said detectable moietyrelative the level of said detectable moiety or detectable agent in thestandard control.

EXAMPLES Example 1. Preparation of (Cmpd 1),dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-3″-ylN-(2,5-dichlorophenyl)carbamate

Step 1: Preparation of Ketone Cmpd 1a,3-[(tert-butyldiphenylsilyl)oxy]cyclohexan-1-one

A 50-mL, recovery flask equipped with a stirbar, rubber septum, andargon inlet was charged with 3-hydroxycyclohexan-1-one (Karmee, S. K.;van Oosten, R.; Hanefeld, U. Tetrahedron: Asymm. 2011, 22, 1736-1739)(0.300 g, 2.63 mmol, 1.0 equiv), N,N-dimethylformamide (10 mL),imidazole (0.358 g, 5.26 mmol, 2.0 equiv), and cooled to 0° C.t-Butyl(chloro)diphenyl silane (0.820 mL, 3.15 mmol, 1.2 equiv) wasadded rapidly dropwise and the reaction mixture was allowed to warm toslowly warm to rt over ca 1 h and stir at rt overnight. The reactionmixture was diluted with 30 mL of EtOAc and 30 mL of H₂O. The aqueouslayer was separated and extracted with three 20-mL portions of EtOAc.The combined organic phases were washed with 20 mL of satd aq NaClsolution, dried over MgSO₄, filtered, and concentrated to a pale yellowliquid. Purification via column chromatography on 120 g of silica gel(gradient elution with 0-5% EtOAc/hexanes) afforded 0.800 g (82%) ofCmpd 1a as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 7.65-7.70 (m, 4H),7.37-7.48 (m, 6H), 4.21 (app. quin, J=4.9 Hz, 1H), 2.45 (d, J=4.9 Hz,2H), 2.33-2.41 (m, 1H), 2.22-2.31 (m, J=5.3 Hz, 1H), 2.09-2.21 (m, 1H),1.76-1.82 (m, 2H), 1.60-1.71 (m, 1H), 1.08 ppm (s, 9H); LRMS (ESI) m/z[M+H]⁺ calcd for C₂₂H28OSi: 353.2; found: 353.1.

Step 2. Preparation of Trioxolane Cmpd 1b,tert-butyl({dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-3″-yloxy})diphenylsilane

A 50-mL, recovery flask equipped with a stirbar was charged withadamantanone O-methyloxime (Vennerstrom, J. L.; Dong, Y.; Chollet, J.;Matile, H.; Padmanilayam, M.; Tang, Y.; Charman, W. N. Preparation ofspiro and dispiro 1,2,4-trioxolane as antimalarials. U.S. Pat. Appl.Publ., 20040186168, 23 Sep. 2004) (0.270 g, 1.51 mmol, 2 equiv), ketoneCmpd 1a (0.266 g, 0.755 mmol, 1.0 equiv), and CCl₄ (15 mL). The mixturewas cooled at 0° C. while ozone was bubbled through the solution (0.6L/min, 30% power). After 10 min of reaction, an additional portion ofoxime was added (0.100 g, 0.558 mmol, 0.74 equiv) and bubbling of ozonewas continued for an additional 20 min (30 min total reaction time). Thereaction mixture was sparged with O₂ at 0° C. for 5 min, and with argonwhile warming to rt over 10 min. The reaction mixture was thenconcentrated to afford a colorless oil. Purification via columnchromatography on 25 g of silica gel (gradient elution with 0-10%EtOAc/hexanes) and then on 40 g of silica gel (gradient elution with0-10% EtOAc/hexanes) afforded 0.416 g (90%) of Cmpd 1b as a colorlessoil: ¹H NMR (400 MHz, CDCl₃) δ 7.68 (td, J=7.7, 1.5 Hz, 4H), 7.35-7.45(m, 6H), 3.88-3.97 (m, 1H), 3.76-3.85 (m, 1H), 1.44-2.15 (m, 20H),1.20-1.32 (m, 3H), 1.07 ppm (s, 9H); LRMS (ESI) m/z [M+Na]⁺ calcd forC₃₂H₄₂OSi: 541.3; found: 541.3.

Step 3: Preparation of Alcohol Cmpd 1c,tert-butyl({dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-3″-yloxy})diphenylsilane

A 50-mL, recovery flask equipped with a stirbar and argon inlet adapterwas charged with silyl ether Cmpd 1b (0.391 g, 0.754 mmol, 1.0 equiv),THF (10 mL), and cooled to 0° C. A solution of TBAF (1.0 M in THF, 1.13mL, 1.13 equiv) was added dropwise via syringe and the reaction wasstirred at 0° C. for 5 min, allowed to warm to rt for 10 min, andstirred at rt. After 1 h, additional TBAF (1.0 M in THF, 2.0 mL, 2.0mmol, 2.6 equiv) was added via syringe. The reaction was stirred at rtfor another 1 h. Another portion of TBAF (1.0 M in THF, 2.0 mL, 2.0mmol, 2.6 equiv) added. The reaction was stirred at rt for 1 h. Thereaction mixture was concentrated to ca 5 mL and stirring was continuedat rt for 1 h. The reaction mixture was diluted with 30 mL of EtOAc and20 mL of H₂O and 5 mL satd aq NaCl solution. The aqueous layer wasseparated and extracted with three 20-mL portions of EtOAc. The combinedorganic phases were washed with 30 mL of satd aq NaCl solution, driedover MgSO₄, filtered, and concentrated to afford a colorless oil.Purification via column chromatography on 25 g of silica gel (elutionwith 15% EtOAc/hexanes) afforded 0.221 g (94%) of Cmpd 1c as a colorlessoil: ¹H NMR (400 MHz, CDCl₃) δ 3.98 (app tt, J=7.3, 3.7 Hz, 1H),1.47-2.09 ppm (m, 23H); LRMS (ESI) m/z [M+Na]⁺ calcd for C₁₆H₂₄O₄:303.2; found: 303.1.

Step 4: Preparation of Carbamate Cmpd 1

A 20-mL, scintillation vial equipped with a screw cap and stirbar wascharged with alcohol Cmpd 1c (0.060 g, 0.210 mmol, 1.0 equiv), toluene(1 mL), pyridine (20 μL, 0.210 mmol, 1 equiv), and 2,5-dichlorophenylisocyanate (0.080 g, 0.430 mmol, 2 equiv). The reaction mixture wasstirred at rt for 18 h. The resulting cloudy reaction mixture wasfiltered with the aid of 50 mL of EtOAc. The filtrate was washed with 20mL of H₂O. The aqueous layer was extracted with three 20-mL portions ofEtOAc. The combined organic phases were washed with 20 mL of satd aqNaCl solution, dried over MgSO₄, filtered, and concentrated to a yellowoil. Purification via column chromatography on 50 g of silica gel(elution with 7% EtOAc/hexanes) afforded 0.077 g (79% yield) of Cmpd 1as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 8.28 (m, 1H), 7.28 (dd,J=8.0, 2.0 Hz, 1H), 7.11 (s, 1H), 6.97 (ddd, J=8.0, 2.4, 1.6 Hz, 1H),4.98-5.05 (m, 1H), 2.26-2.34 (m, 2H), 1.41-2.07 (m, 20H); LRMS (ESI) m/z[M+H]⁺ calcd for C₂₃H₂₇C₁₂NO₅: 468.1; found: 468.6. Some peakscorresponding to the minor isomer were observed: 1H NMR (400 MHz,CDCl₃): δ 7.09 (s, 1H), 4.86-4.92 (m, 1H).

Example 2. Preparation of (Cmpd 2),3″-ethenyldispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-3″-ylN-(2,5-dichlorophenyl)carbamate

Step 1: Preparation of Trioxolane Cmpd 2a,trispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane-3″,2′″-[1,3]dioxolane]

A 500-mL, round-bottomed flask equipped with a stirbar was charged witha solution of 1,4-dioxaspiro[4.5]decan-7-one (Takagi, H.; Hayashi, T.;Mizutani, T.; Masuda, H.; Ogoshi, H. J. Chem. Soc., Perkin Trans 1,1999, 1885-1892) (5.75 g, 36.8 mmol, 2.0 equiv) in CCl₄ (180 mL).Adamantanone O-methyloxime (Vennerstrom, J. L.; Dong, Y.; Chollet, J.;Matile, H.; Padmanilayam, M.; Tang, Y.; Charman, W. N. Preparation ofspiro and dispiro 1,2,4-trioxolane as antimalarials. U.S. Pat. Appl.Publ., 20040186168, 23 Sep. 2004) (3.30 g, 18.4 mmol, 1.0 equiv) wasadded and the solution was cooled to 0° C. Ozone (0.6 L/min dial, 30%power) was bubbled through the solution for 2 h. The reaction mixturewas sparged with O₂ for 10 min, sparged with argon while being allowedto warm to rt over 10 min, and concentrated to afford a colorless oil.Purification via column chromatography on 220 g of silica gel (gradientelution with 5-20% EtOAc/hexanes) afforded 0.265 g of Cmpd 2a as acolorless oil: ¹H NMR (300 MHz, CDCl₃) 3.99-4.04 (m, 1H), 3.87-3.96 (m,3H), 1.47-2.08 (m, 22H); LRMS (ESI) m/z [M+H]⁺ calcd for C₁₈H₂₆O₃:323.2; found 323.1.

Step 2: Preparation of Ketone Cmpd 2b,dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-3″-one

A 100-mL, round-bottomed flask equipped with a stirbar, rubber septum,and argon inlet was charged with the acetal Cmpd 2a (1.0 g, 3.1 mmol,1.0 equiv), CH₂Cl₂ (16 mL), acetone (4 mL), and iron(III) chloridehexahydrate (2.80 g, 10.4 mmol, 3.3 equiv). The resulting orangereaction mixture was stirred at rt for 1 h. The reaction mixture wasdiluted with 30 mL of CH₂Cl₂ and 20 mL of satd aq NH₄Cl. The aqueouslayer was separated and extracted with three 30-mL of portions ofCH₂Cl₂. The combined organic phases were washed with 40 mL of satd aqNaCl solution, dried over MgSO₄, filtered, and concentrated to afford ayellow oil. Purification via column chromatography on 40 g of silica gel(gradient elution with 0-5% EtOAc/hexanes) afforded 0.517 g of Cmpd 2bas a pale yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 2.72 (s, 2H), 2.35 (t,J=8.0 Hz, 2H), 1.69-2.06 (m, 18H); LRMS (ESI) m/z [M+H]⁺ calcd forC₁₆H₂₂O₄: 279.1; found: 279.0.

Step 3: Preparation of Alcohol Cmpd 2c,3″-ethenyldispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-3″-ol

A 25-mL, recovery flask equipped with a stirbar, rubber septum, andargon inlet needle was charged with Et₂O (2 mL) and a solution of vinylmagnesium bromide (1.0 M in THF, 0.89 mL, 0.89 mmol, 3 equiv). Themixture was cooled to −78° C. while a solution of ketone Cmpd 2b (0.083g, 0.30 mmol, 1 equiv) in Et₂O (1.0 mL) was added dropwise via syringe.The reaction was stirred at −78° C. for 1 h. The reaction mixture wasquenched by dropwise addition of MeOH (36 μL, 0.89 mmol, 3 equiv) andstirred at −78° C. for 10 min. Another portion of vinyl magnesiumbromide (1.0 M in THF, 1.8 mL, 1.8 mmol, 1.8 equiv) was added dropwisevia syringe and the reaction mixture was stirred at −78° C. for 1 h.MeOH (84 μL, 2.1 mmol, 7 equiv) was added dropwise via syringe and thereaction mixture was stirred at −78° C. for 10 min. Another portion ofvinyl magnesium bromide (1.0 M in THF, 4.0 mL, 4.0 mmol, 14 equiv) wasadded dropwise via syringe and the reaction mixture was stirred at −78°C. for 45 min. The reaction mixture was then diluted with 20 mL of Et₂Oand 20 mL of satd aq NH₄Cl solution. The aqueous layer was separated andextracted with three 20-mL portions of Et₂O. The combined organic phaseswere washed with 30 mL of satd aq NaCl solution, dried over MgSO₄,filtered, and concentrated to afford a cloudy, pale-yellow oil.Purification via column chromatography on 25 g of silica gel (gradientelution with 2-20% EtOAc/hexanes) afforded 0.040 g of Cmpd 2c as a paleyellow oil: ¹H NMR (CDCl₃, 400 MHz) δ 5.90 (dd, J=16.0, 11.2 Hz, 1H),5.31 (d, J=17.0 Hz, 1H), 5.05 (d, J=10.8 Hz, 1H), 2.70 (s, 1H),1.57-2.02 (m, 21H), 1.43 (td, J=13.0, 4.8 Hz, 1H); LRMS (ESI) m/z [M+H]⁺calcd for C₁₈H₂₆O₄: 307.4; found: 307.1.

Step 4: Preparation of Carbamate Cmpd 2

A 20-mL, scintillation vial equipped with a stirbar and screw cap wascharged with alcohol Cmpd 2c (0.030 g, 0.1 mmol, 1 equiv), toluene (0.5mL), pyridine (8 μL, 0.1 mmol, 1 equiv), and 2,5-dichlorophenylisocyanate (0.037 g, 0.20 mmol, 2 equiv). The resulting white slurry wasstirred at rt for 18 h then heated at 50° C. for 4.5 h. The reactionmixture was then diluted with 2 mL of H₂O. The resulting precipitate wasremoved via filtration through a 1.5″×2″ pad of Celite with the aid of20 mL of Et₂O and 10 mL of H₂O. The aqueous phase of the filtrate wasseparated and extracted with three 20-mL portions of Et₂O. The combinedorganic phases were washed with 30 mL of satd aq NaCl solution, driedover MgSO₄, filtered and concentrated to afford a cloudy oil.Purification via column chromatography on 12 g of silica gel (gradientelution with 2-20% EtOAc/hexanes) afforded 0.016 g (53% recovered SM) ofstarting material and 0.006 g (13%) of desired carbamate Cmpd 2 as acolorless oil: ¹H NMR (400 MHz, CDCl₃) δ 8.24 (d, J=2.4 Hz, 1H), 7.24(m, 1H), 7.11 (br s, 1H), 6.95 (dd, J=9.0, 4.0 Hz, 1H), 6.19 (dd,J=16.8, 11.2 Hz, 1H), 5.25 (d, J=18.4 Hz, 1H), 5.21 (d, J=11.2 Hz, 1H),2.80 (d, J=14.4 Hz, 1H), 2.22 (d, J=13.6 Hz, 1H), 1.47-2.12 (m, 20H);LRMS (ESI) m/z [M]⁺ calcd for C₂₅H₂₉Cl₂NO₅: 493.1; found: 493.3.

Example 3. Preparation of (Cmpd 3),(3″S,5″S)-5″-tert-butyldispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-3″-ylN-(2,5-dichlorophenyl)carbamate

Step 1: Preparation of Trioxolane Cmpd 3a,tert-butyl[(3″S,5″S)-5″-tert-butyldispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-3″-yloxy]dimethylsilane

A 25-mL, pear-shaped flask equipped with a stirbar was charged withadamantanone O-methyloxime (Vennerstrom, J. L.; Dong, Y.; Chollet, J.;Matile, H.; Padmanilayam, M.; Tang, Y.; Charman, W. N. Preparation ofspiro and dispiro 1,2,4-trioxolane as antimalarials. U.S. Pat. Appl.Publ., 20040186168, 23 Sep. 2004) (0.153 g, 0.854 mmol, 2.1 equiv) and(3S,5S)-3-tert-butyl-5-[(tert-butyldimethylsilyl) oxy]cyclohexan-1-one(Hareau, G. P-J.; Koiwa, M.; Hikichi, S.; Sato, F. J. Am. Chem. Soc.,1999, 121, 3640-3650)(0.116 g, 0.4 mmol, 1.0 equiv), in CCl₄ (4 mL). Thesolution was cooled at 0° C. while ozone (0.6 L/min, 30% power) wasbubbled through the solution for 50 min. An addition portion of theoxime (0.155 g, 0.865 mmol, 2.1 equiv) was added in a single portion.Ozone was bubbled through the reaction mixture at 0° C. for anadditional 1 h. O₂ was bubbled through the solution while stirring at 0°C., then the reaction mixture was allowed to warm to rt while argon wasbubbled through the reaction mixture. The reaction solution wasconcentrated to afford a colorless oil. Purification via columnchromatography on 12 g of silica gel (gradient elution with 0-10%EtOAc/hexanes), and purification of mixed fractions on 12 g silica gel(elution with 5% EtOAc/hexanes) and on 25 g silica gel (elution with 5%EtOAc/hexanes) afforded 0.042 g of Cmpd 3a as a colorless oil: ¹H NMR(CDCl₃, 400 MHz) δ 4.28 (m, 1H), 2.39 (s, 1H), 1.56-2.17 (m, 18H), 1.21(t, J=12.4 Hz, 1H), 1.09 (td, J=12.4, 2.8 Hz, 1H), 0.91 (s, 9H), 0.86(s, 9H), 0.05 (s, 3H), 0.04 (s, 3H); LRMS (ESI) m/z [M+H+H₃COH]⁺ calcdfor C₂₆H₄₆O₄Si: 483.3; found: 483.3.

Step 2: Preparation of Cmpd 3b, (3″S*,5″S*)-5″-tert-butyldispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-3″-ol

A 25-mL, recovery flask equipped with a stirbar, rubber septum, andargon inlet needle was charged with a solution of silyl ether Cmpd 3a(0.042 g, 0.093 mmol, 1.0 equiv) in THF (1.5 mL). The solution wascooled at 0° C. while a solution of TBAF (1.0 M in THF, 0.140 mL, 0.140mmol, 1.5 equiv) was added via syringe. The reaction mixture was allowedto warm to rt and was stirred at rt for 30 min. Another portion of TBAF(1.0 M in THF, 0.230 mL, 0.230 mmol, 2.5 equiv) was added via syringeand the reaction mixture was stirred at rt for 42 h. Additional TBAF wasadded (1.0 M in THF, 0.190 mL, 0.190 mmol, 2 equiv) and the reactionmixture was heated at 40° C. for 5 h. The reaction mixture was allowedto cool to rt and diluted with 20 mL of Et₂O and 20 mL of H₂O. Theaqueous layer was separated and extracted with three 20-mL portions ofEt₂O. The combined organic phases were washed with 30 mL of satd aq NaClsolution, dried over MgSO₄, filtered, and concentrated to afford acolorless oil. Purification via column chromatography on 12 g of silicagel (gradient elution with 0-10% EtOAc/hexanes) afforded 0.020 g (48%)of the silyl ether starting material and 0.013 g (42%) of Cmpd 3b as acolorless oil: ¹H NMR (400 MHz, CDCl₃) δ 4.27 (dt, J=10.0, 2.8 Hz, 1H),3.40 (d, J=10.4 Hz, 1H), 1.71-2.11 (m, 19H), 1.29 (t, J=12.4 Hz, 1H),1.16 (td, J=13.2, 2.8 Hz, 1H), 0.89 (s, 9H); LRMS (ESI) m/z [M+H]⁺ calcdfor C₂₀H₃₂O₄: 337.2; found: 337.1.

Step 3: Preparation of Carbamate Cmpd 3

A 20-mL, scintillation vial equipped with a screw cap and stirbar wascharged with a solution of alcohol Cmpd 3b (0.016 g, 0.048 mmol, 1.0equiv) in toluene (1 mL) and pyridine (4 μL, 0.05 mmol, 1 equiv).2,5-dichlorophenyl isocyanate (0.018 g, 0.095 mmol, 2 equiv) was addedand the reaction mixture was stirred at rt for 20 h. Additional2,5-dichlorophenyl isocyanate (0.020 g, 0.1 mmol, 2 equiv) and 1 equivof pyridine (4 μL, 0.05 mmol, 1 equiv) were added and the reaction asstirred at rt for an additional 22 h. At 42 hr total reaction time,additional 2,5-dichlorophenyl isocyanate (0.020 g, 0.1 mmol, 2 equiv)was added and the reaction was stirred at 40° C. for 4 h. The reactionmixture was diluted with 5 mL of H₂O and 5 mL of Et₂O. The resultingmixture was filtered through a 3″ by 3″ pad of celite with the aid of 50mL Et₂O and 20 mL of H₂O. The resulting aqueous layer was separated andextracted with three 20-mL portions of Et₂O. The combined organic phaseswere washed with 20 mL of satd aq NaCl solution, dried over MgSO₄,filtered, and concentrated to afford a white slurry. This material wassuspended in hexanes and filtered. The resulting filtrate wasconcentrated to afford a cloudy pale yellow oil. Purification via columnchromatography on 12 g of silica gel (gradient elution with 2-20%EtOAc/hexanes) and then on 25 g of silica gel (gradient elution with5-10% EtOAc/hexanes) afforded 0.013 g (52%) of Cmpd 3 as a colorlesssolid: ¹H NMR (400 MHz, CDCl₃) δ 8.27 (s, 1H), 7.26 (d, J=8.4 Hz, 1H),7.11 (br s, 1H), 6.97 (dd, J=8.4, 2.4 Hz, 1H), 5.28 (m, 1H), 2.36 (dd,J=14.0, 1.2 Hz, 1H), 1.54-2.09 (m, 16H), 1.25-1.35 (m, 2H), 0.92 (s,9H).

Example 4. Preparation of (Cmpd 4),(3″R*,5″S*)-5″-{[(2,5-dichlorophenyl)carbamoyl]oxy}dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-3″-ylN-(2,5-dichlorophenyl)carbamate

Step 1: Preparation of Cmpd 4a,3″-(acetyloxy)dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-5″-ylacetate

A 50-mL, recovery flask was charged with(1S*,3R*)-3-(acetyloxy)-5-oxocyclohexyl acetate (Hilpert, H.; Wirz, B.Tetrahedron, 2001, 57, 681-694)(0.176 g, 0.8 mmol, 1.0 equiv.), CCl₄(6.882 ml), and adamantanone O-methyloxime (Vennerstrom, J. L.; Dong,Y.; Chollet, J.; Matile, H.; Padmanilayam, M.; Tang, Y.; Charman, W. N.Preparation of spiro and dispiro 1,2,4-trioxolane as antimalarials. U.S.Pat. Appl. Publ., 20040186168, 23 Sep. 2004) (0.145 g, 0.809 mmol, 1equiv). The reaction mixture was cooled at 0° C. while ozone (0.6 L/min,30% power) was bubbled through solution for 45 min. Additional oxime(0.175 g, 0.976 mmol, 1 equiv) was added as a solid in a single portionand ozone was bubbled through the reaction mixture for an additional 45min at 0° C. The reaction was sparged with O₂ for 5 min, allowed to warmto rt over 10 min while sparging with argon, and concentrated to affordCmpd 4a as a colorless oil. Purification via column chromatography on 12g of silica gel (elution with 15% EtOAc/hexanes) afforded 0.258 g (83%)of a viscous oil: ¹H NMR (400 MHz, CDCl₃) δ 4.82 (tt, J=4.5, 11.7 Hz,2H), 2.30-2.38 (m, 1H), 2.23-2.29 (m, J=1.6 Hz, 2H), 1.97-2.02 (m, 6H),1.61-1.95 (m, 16H), 1.38 (q, J=11.5 Hz, 1H); LRMS (ESI) m/z [M+Na]⁺calcd for C₂₀H₂₈O₇: 403.2; found: 403.1.

Step 2: Preparation of Cmpd 4b,(3″R*,5″S*)-dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-3″,5″-diol

A 20-mL, scintillation vial equipped with a screw cap and stirbar wascharged with bis-acetate Cmpd 4a, methanol (12 mL), and K₂CO₃ (0.278 g,2.01 mmol, 5.0 equiv) and the resulting mixture was stirred at 1.5 h.The reaction mixture was diluted with 30 mL of EtOAc and 20 mL of H₂O.The aqueous layer was separated and extracted with four 25-mL portionsof EtOAc. The combined organic phases were washed with 20 mL of satd aqNaCl solution, dried over MgSO₄, filtered, and concentrated to afford apale yellow oil. A solution of this material in CH₂Cl₂ was depositedonto 5 g of silica gel. The resulting free flowing powder wastransferred to the top of a 25 g column of silica gel. Gradient elutionwith 50-100% EtOAc/hexanes afforded 0.072 g (60%) of Cmpd 4b as a whitesolid: ¹H NMR (400 MHz, CD₃OD) δ 3.61 (tt, J=4.4, 11.6 Hz, 2H), 2.21(ttd, J=1.9, 4.0, 11.5 Hz, 1H), 2.09-2.17 (m, 2H), 2.02 (d, J=12.5 Hz,2H), 1.87-1.97 (m, 4H), 1.70-1.85 (m, 8H), 1.57 (t, J=12.5 Hz, 2H), 1.22(q, J=11.5 Hz, 1H); LRMS (ES) m/z [M+Na]⁺ calcd for C₁₆H₂₄O₅: 319.2;found: 319.0.

Step 3: Preparation of Cmpd 4

A 20-mL, scintillation vial equipped with a stirbar and screw cap wascharged with diol Cmpd 4b (0.013 g, 0.044 mmol, 1.0 equiv), pyridine(1.5), and 2,5-dichlorophenyl isocyanate (0.040 g, 0.219 mmol, 5 equiv).The reaction mixture was stirred rt for 2 h. Additional2,5-dichlorophenyl isocyanate (0.020 g, 0.109 mmol, 2.5 equiv) was addedand the reaction mixture was stirred at rt for 22 h. The reactionmixture was treated with an additional 2,5-dichlorophenyl isocyanate(0.040 g, 0.219 mmol, 5 equiv) and heated to 50° C. for 2 h. Additional2,5-dichlorophenyl isocyanate (0.100 g, 0.532 mmol, 12 equiv) and DMAP(0.020 g, 0.2 mmol, 3.7 equiv) were added and the reaction mixture wasstirred at 50° C. for 29 h. The reaction mixture was diluted with 20 mLof EtOAc and 15 mL of H₂O and the resulting slurry was filtered througha 2″×2″ pad of Celite. The aqueous phase was separated and extractedwith three 20-mL portions of EtOAc. The combined organic phases werewashed with 35 mL satd aq NaCl solution, dried over Na₂SO₄, filtered,and concentrated to afford a white solid. A solution of this material in10 mL of CH₂Cl₂ was deposited onto 5 g of silica gel. The resulting freeflowing powder was loaded on top of a 25 g column of silica gel.Gradient elution with 5-15% EtOAc/hexanes afforded 0.016 g (58%) of Cmpd4 as a white solid: ¹H NMR (400 MHz, CDCl₃): δ 8.25 (d, J=1.1 Hz, 2H),7.23-7.27 (m, 4H), 7.09 (s, 2H), 6.97 (dd, J=8.5, 2.5 Hz, 2H), 4.91 (tt,J=11.5, 4.5 Hz, 2H), 2.53-2.61 (m, 1H), 2.40-2.46 (m, 2H), 1.52-2.01 (m,16H), 1.22-1.28 ppm (m, 1H).

Example 5. Preparation of (Cmpd 5),dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-3″-ylN-ethylcarbamate

A 20-mL, scintillation vial equipped with a stirbar and screw cap wascharged with alcohol Cmpd 1c, toluene (1 mL), and pyridine (50 μL, 0.62mmol, 1.5 equiv). Ethyl isocyanate (70 μL, 0.83 mmol, 2.1 equiv) wasadded via syringe and the resulting mixture was stirred at rt for 17 h.Additional ethyl isocyanate (0.100 mL, 1.26 mmol, 3 equiv) was added andthe resulting mixture was heated at 50° C. for 72 h. After 89 h totalreaction time, the reaction mixture was diluted with 20 mL of CH₂Cl₂ and20 mL of H₂O. The aqueous layer was separated and extracted with three20-mL portions of CH₂Cl₂. The combined organic phases were washed with30 mL of satd aq NaCl solution, dried over MgSO₄, filtered, andconcentrated to afford a pale yellow oil. Purification via columnchromatography on 25 g of silica gel (gradient elution with 20-25%EtOAc/hexanes) afforded the following: ¹H NMR (CDCl₃, 400 MHz) δ4.83-4.89 (m, 1H), 4.71 (m, 1H), 4.64 (m, 1H), 3.18-3.22 (m, 4H),2.15-2.24 (m, 2H), 1.85-2.03 (m, 18H), 1.44-1.81 (m, 22H), 1.09-1.13 (m,6H); LRMS (ESI) m/z [M+Na]⁺ calcd for C₁₉H₂₉NO₅: 374.2; found: 374.1.

Example 6. Preparation of (Cmpd 6)dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-3″-yl2-[(S)-[2,8-bis(trifluoromethyl)quinolin-4-yl](hydroxy)methyl]piperidine-1-carboxylate

Step 1: Preparation of P-Nitrophenyl Carbonate Cmpd 6a(dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-3″-yl4-nitrophenyl carbonate

To a solution of alcohol Cmpd 1c (0.085 g, 0.30 mmol, 1.0 equiv) inCH₂Cl₂ (5.0 mL) was added triethylamine (71 μL, 0.51 mmol, 1.7 equiv),p-nitrophenyl chloroformate (0.103 g, 0.51 mmol, 1.7 equiv), followed byDMAP (0.037 g, 0.30 mmol, 1 equiv). The reaction mixture was stirred atrt for 22 h, and then diluted with CH₂Cl₂ and washed with a threeportions of satd aq NaHCO₃ solution three times, and one portion of satdaq NaCl solution. The organic layer was dried over MgSO₄, filtered, andevaporated. The crude oil was purified by column chromatography on 25 gof silica gel (gradient elution with 0-30% EtOAc/hexanes with 1% Et₃N)to obtain 0.130 g of Cmpd 6a (96%) (as a 60:40 mixture of diastereomers)as a colorless oil: ¹H NMR (400 MHz, CDCl₃): δ 8.27 (d, 2H, J=8 Hz),7.39 (m, 2H), 4.94 (m, 0.6H), 4.83 (m, 0.4H), 2.36 (t, 1H, J=12 Hz),1.99-1.50 (m, 21H); LRMS (ESI) m/z [2M+Na]⁻ calcd for C₄₆H₅₄N₂O₁₆:913.34; found 913.4.

Step 2: Preparation of Cmpd 6

A 20-mL, scintillation vial equipped with stirbar and screw cap wascharged with a solution of carbonate Cmpd 6a (0.058 g, 0.13 mmol, 1equiv) in DMF (1 mL) and N,N-diisopropylethylamine (60 μL, 0.33 mmol,2.5 equiv). Mefloquine hydrochloride (0.081 g, 0.195 mmol, 1.5 equiv)was added as a solid in a single portion and the reaction mixture wasstirred at rt for 18 h. The reaction mixture was diluted with 30 mL ofEtOAc and washed with three 20-mL portions of satd aq NaHCO₃ and 20 mLsatd aq NaCl solution. The organic phase was dried over MgSO₄, filteredand concentrated to afford a yellow oil. Purification via columnchromatography on 25 g of silica gel (elution with 10% EtOAc/hexanes)afforded 0.070 g (89%) of Cmpd 6 as a colorless solid: ¹H NMR (400 MHz,CDCl₃) δ 8.60-8.70 (m, 1H), 8.11-8.17 (m, 1H), 8.05-8.09 (m, 1H),7.68-7.77 (m, 1H), 5.85-5.94 (m, 1H), 4.81-4.93 (m, 1H), 4.72-4.81 (m,1H), 4.19-4.31 (m, 1H), 3.85-4.00 (m, 1H), 3.29-3.46 (m, 1H), 2.97-3.26(m, 1H), 2.08-2.26 (m, 1H), 1.31-2.07 (m, 25H), 0.77-0.92 ppm (m, 1H);LRMS (ESI) m/z [M+H]⁺ calcd for C₃₄H₃₈F₆N₂O₆: 685.3; found: 685.2.

Example 7. Preparation of (Cmpd 7),dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-3″-ylN-{4-[(6-methoxyquinolin-8-yl)amino]pentyl}carbamate

A 4-mL, scintillation vial equipped with a stirbar and screw cap wascharged with a solution of p-nitrophenyl carbonate Cmpd 6a (0.026 g,0.061 mmol, 1 equiv) in DMF (0.7 mL) and i-Pr₂NEt (37 μL, 0.21 mmol, 3.5equiv), and primaquine bisphosphate (0.041 g, 0.091 mmol, 1.5 equiv).The reaction mixture as stirred at rt for 18 h then diluted with 20 mLof EtOAc. The organic phase was washed with three 20-mL portions of satdaq NaHCO₃ solution and 20 mL of satd aq NaCl solution. The organic phasewas dried of MgSO₄, filtered, and concentrated to afford a yellow oil.Purification via column chromatography on 12 g of silica gel (elutionwith 70% EtOAc/hexanes) and purification of mixed fractions on 12 g ofsilica gel (gradient elution 10-20% EtOAc/hexanes) afforded 0.023 g(68%) of Cmpd 7 as a colorless solid: ¹H NMR (400 MHz, CD₃OD) δ 8.50(dd, J=4.2, 1.6 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.39 (dd, J=8.2, 4.2Hz, 1H), 6.48-6.51 (m, 1H), 6.35-6.38 (m, 1H), 4.72-4.81 (m, 1H),4.54-4.66 (m, 1H), 3.85-3.90 (m, 3H), 3.61-3.72 (m, 1H), 3.07-3.16 (m,2H), 2.09-2.19 (m, 1H), 1.54-2.09 (m, 24H), 1.26-1.50 ppm (m, 6H); LRMS(ESI) m/z [M+H]⁺ calcd for C₃₂H₄₃N₃O₆: 566.3; found: 566.3.

Example 8. Preparation of (Cmpd 8),3-(dibutylamino)-1-[1,3-dichloro-6-(trifluoromethyl)phenanthren-9-yl]propyldispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-3″-ylcarbonate

A 4-mL, scintillation vial equipped with a screw cap and stirbar wascharged with p-nitrophenyl carbonate Cmpd 6a (0.008 g, 0.02 mmol, 1.0equiv), DMF (0.250 mL), halofantrine hydrochloride (0.010 g, 0.02 mmol,1.0 equiv), and i-Pr₂NEt (20 ul, 0.12 mmol, 6.4 equiv). The reactionmixture was stirred at rt for 20 h. DMAP (0.002 g, 0.02 mmol, 1.0 equiv)was added and the reaction was heated at 38° C. for 48 h. The reactionmixture was diluted with 20 mL of EtOAc and washed with four 10-mLportions of 1 M aq NaOH solution until the aqueous washes no longerappeared yellow. The organic phase was washed with 20 mL of satd aq NaClsolution, dried over MgSO₄, filtered, and concentrated to afford a whiteresidue. A solution of this residue in 10 mL of 10% methanol in CH₂Cl₂was deposited onto 5 g of silica gel. The resulting free flowing powderwas loaded on top of a 12 g column of silica gel and elution with 10%EtOAc/hexanes afforded 0.013 g (89%) of Cmpd 8 (as a mixture of 4diastereomers): For the mixture of diastereomers with a higher R_(f): ¹HNMR (400 MHz, CDCl₃) δ 8.87 (s, 2H), 8.56 (d, J=1.3 Hz, 2H), 8.42 (d,J=8.8 Hz, 2H), 8.33 (d, J=1.3 Hz, 2H), 7.97-7.84 (m, 2H), 7.76-7.68 (m,2H), 6.53-6.41 (m, 2H), 4.78 (ddd, J=4.2, 9.9, 14.5 Hz, 1H), 4.64 (tt,J=4.3, 10.8 Hz, 1H), 3.05-2.80 (m, 2H), 2.79-2.61 (m, J=5.3 Hz, 2H),2.53-2.39 (m, J=12.1 Hz, 4H), 2.39-2.30 (m, J=2.7, 8.1 Hz, 4H), 2.26 (d,J=11.0 Hz, 2H), 2.03-1.16 (m, 62H), 0.90 (t, J=6.1 Hz, 12H); LRMS (ESI)m/z [M+H]⁺ calcd for C₄₃H₅₂F₃NO₆: 806.31; found: 806.3. For the mixtureof diastereomers with a lower R_(f): ¹H NMR (300 MHz, CDCl₃): δ 8.90 (s,2H), 8.59 (s, 2H), 8.44 (d, J=8.9 Hz, 2H), 8.37 (d, J=6.0 Hz, 2H), 7.93(s, 2H), 7.76 (s, 2H), 6.50 (s, 2H), 4.73-4.87 (m, 1H), 4.57-4.73 (m,1H), 1.99-2.99 (m, 14H), 1.19-1.98 (m, 62H), 0.91 ppm (m., 12H); LRMS(ESI) m/z calcd for C₄₃H₅₂F₃NO₆: 806.31; found: 806.2.

Example 9. Preparation of (Cmpd 9),dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-3″-ylN-(1-{1-[2-oxo-1-(2,3,5,6-tetrafluorophenoxy)heptan-3-yl]-1H-1,2,3-triazol-4-yl}cyclohexyl)carbamate)

To a solution of HN3019 hydrochloride (Deu, E.; Leyva, M. J.; Albrow, V.E.; Rice, M. J.; Ellman, J. A.; Bogyo, M. Chem. Biol. 2010, 17,808-819)(0.023 g, 0.048 mmol, 1 equiv) in anhydrous DMF (1 mL) was addedi-Pr₂NEt (18 μL, 0.11 mmol, 2.3 equiv) followed by p-nitrophenylcarbonate Cmpd 6a (0.021 g, 0.048 mmol, 1 equiv) in DMF (1 mL), and DMAP(0.001 g, 0.010 mmol, 2 equiv). The yellow solution was stirred at rtfor 20 h, at which point additional i-Pr₂NEt (9.0 μL, 0.005 mmol, 1equiv) and DMAP (0.001 g, 0.01 mmol, 2 equiv) were added. The reactionmixture was stirred at rt for an additional 24 h. The reaction mixturewas diluted with 10 mL of satd aq NaHCO₃ solution and 10 mL of EtOAc.The organic phase was separated and washed sequentially with 10 mL of 1M aq HCl solution, 10 mL of 1 M aq NaOH solution, and 15 mL of satd aqNaCl solution. The organic phase was dried over MgSO₄, filtered, andconcentrated to afford a pale yellow oil. Purification via columnchromatography on 12 g of silica gel (gradient elution with 10-25%EtOAc/hexanes) afforded 0.013 g (36%) of Cmpd 9 (as a mixture ofisomers) as a viscous/glassy oil: ¹H NMR (400 MHz, CDCl₃): δ 7.65 (s,1H), 6.81 (m, 1H), 5.53 (br s, 1H), 4.96 (s, 1H), 4.87 (m, 1H), 4.73 (brs, 0.5H), 4.56 (br s, 0.5H), 2.28 (m, 2H), 2.10-1.58 (m, 16H), 1.38-1.19(m, 5H), 0.89 (t, J=4 Hz. 3H); LRMS (ESI) m/z [M+H]⁺ calcd forC₃₈H₄₈F₄N₄O₇: 749.4; found 749.3.

Example 10: Preparation of (Cmpd 10),2-{dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-4″-yl}-3-hydroxy-1,4-dihydronaphthalene-1,4-dione

Step 1. Preparation of Cmpd 10a,2-chloro-3-{dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-4″-yl}-1,4-dihydronaphthalene-1,4-dione

A 20-mL scintillation vial equipped with a stirbar and screw cap wascharged withdispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-4″-carboxylicacid (Tang, Y.; Dong, Y.; Karle, J. M.; DiTusa, C. A.; Vennterstrom, J.L. J. Org. Chem. 2004, 69, 6470-6473) (0.096 g, 0.31 mmol, 1.0 equiv),2,3-dichloro-1,4-naphthoquinone (0.076 g, 0.33 mmol, 1.1 equiv),silver(I) nitrate (0.042 g, 0.25 mmol, 0.8 equiv), and acetonitrile (3mL). The reaction mixture was heated at 80° C. in a preheated vialblock. A solution of ammonium persulfate (0.300 g, 1.32 mmol, 4.2 equiv)in water (2 mL) was added dropwise via syringe and the reaction mixturewas stirred at 80° C. for 10 min. The reaction mixture was allowed tocool to rt and was diluted with 25 mL of EtOAc and 20 mL of H₂O. Theaqueous phase was separated and extracted with two 25-mL portions ofEtOAc and two 25-mL portions of CHCl₃. The combined organic phases weredried over Na₂SO₄, filtered, and concentrated to afford a yellow solid.A solution of this material in 10 mL of 10% MeOH/CH₂Cl₂ was depositedonto 5 g of silica gel. The resulting free flowing powder was loadedatop a column of 12 g of silica gel. Gradient elution with 2-20%EtOAc/hexanes and re-purification of mixed fractions on 25 g of silicagel (elution with 10% EtOAc/hexanes) afforded 0.036 g (24%) of Cmpd 10a(as a mixture of isomers) as a yellow semi solid: ¹H NMR (400 MHz,CDCl₃) δ 8.07-8.16 (m, 2H), 7.70-7.79 (m, 2H), 3.24-3.37 (m, 1H),2.38-2.65 (m, 2H), 2.14-2.23 (m, 1H), 1.88-2.12 (m, 8H), 1.59-1.88 ppm(m, 12H); LRMS (ESI) m/z [M+Na]⁺ calcd for C₂₆H₂₇ClO₅: 477.2; found:477.2.

Step 2: Preparation of Cmpd 10

A 10-mL microwave tube equipped with a stirbar and silicon cap wascharged with chloroquinone Cmpd 10a (0.041 g, 0.1 mmol, 1.0 equiv) andmethanol (4 mL). A solution of potassium hydroxide (0.200 g, 3.56 mmol,40 equiv) in water (2 mL) was added dropwise via syringe over 2 min. Thereaction mixture was heated in the microwave at 65° C. for 4 h. Due toinsolubility of the starting material, the reaction mixture wastransferred to a 50-mL recovery flask and diluted with 15 mL of THF.Additional potassium hydroxide (0.200 g, 3.56 mmol, 40 equiv) in 1 mL ofwater was added. The reaction mixture was heated at 60° C. for 1 h. Thereaction mixture was diluted with 40 mL of EtOAc, 20 mL of H₂O, and 5 mLof 1M aq HCl. The aqueous layer was separated and extracted with three30-mL portions of EtOAc. The combined organic phases were washed with 30mL of satd aq NaCl solution, dried over Na₂SO₄, and concentrated toafford an orange oil. A solution of this material in 10 mL of 10%MeOH/CH₂Cl₂ was deposited onto 5 g of silica gel. The resulting freeflowing powder was loaded atop a 25 g column of silica gel and gradientelution with 0-50% EtOAc/hexanes afforded 0.011 g (28%) of Cmpd 10 (as a60:40 mixture of diastereomers) as a yellow oil: ¹H NMR (400 MHz: CDCl₃)δ 8.11-8.16 (m, 1H), 8.06-8.10 (m, 1H), 7.74-7.79 (m, 1H), 7.66-7.71 (m,1H), 7.47 (s, 1H), 3.04-3.20 (m, 1H), 2.22-2.35 (m, 1H), 2.12-2.19 (m,1H), 1.99-2.10 (m, 4H), 1.91-1.99 (m, 2H), 1.53-1.91 ppm (m, 14H) LRMS(ESI) m/z [M+Na]⁺ calcd for C₂₆H₂₈O₆: 459.2; found 459.2. Resonancescorresponding to the minor isomer were observed at: ¹H NMR (400 MHz,CDCl₃) δ 7.51 (s, 1H), 2.35-2.53 (m, 1H).

Example 11. Preparation of (Cmpd 11),dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-3″-ylN-{2-methoxy-5-[1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl]phenyl}carbamate

Step 1: Preparation of Isocyanate Cmpd 11a,5-(3-isocyanato-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole

A 2-neck, 25-mL, round-bottomed flask equipped with a stirbar, rubbersepta, and reflux condenser fitted with an argon inlet adapter wascharged with triphosgene (0.020 g, 0.1 mmol, 0.5 equiv) dissolved in 4mL of toluene. A solution of2-methoxy-5-[1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl]aniline(Odlo, K.; Hentzen, J.; dit Chabert, J. F.; Ducki, S.; Gani, O. a B. S.M.; Sylte, I.; Skrede, M.; Florenes, V. A.; Hansen, T. V. Bioorg. Med.Chem. 2008, 16, 4829-4838) (0.046 g, 0.1 mmol, 1.0 equiv) in 4 mL oftoluene was added dropwise to this solution at rt. The reaction mixturewas heated to reflux for 4 hours then allowed to cool to rt and quenchedwith 10 mL of H₂O then extracted with three, 15-mL portions of CH₂Cl₂.The organic phases were combined, dried over MgSO₄, and filtered beforeconcentrating to yield an oil, Cmpd 1a, which was carried forwardwithout further purification. LRMS (ESI) m/z [M+H]⁺ calcd forC₁₉H₁₈N₄O₅: 383.1; found: 383.2.

Step 2: Preparation of Carbamate Cmpd 11

A 25-mL, round-bottomed flask equipped with a stir bar, rubber septa,and an argon inlet needle was charged with a solution of alcohol Cmpd 1c(0.049 g, 0.2 mmol, 1.4 equiv) in 2 mL of dry CH₂Cl₂, pyridine (0.050ml, 0.6 mmol, 4.8 equiv) and 4-dimethylaminopyridine (0.004 g, 0.0 mmol,0.2 equiv) under argon. The isocyanate (Cmpd 11a) was then addeddropwise to this reaction mixture in a solution of CH₂Cl₂ (2 mL) and thereaction mixture was heated to 40° C. After 72 hours the reactionmixture was diluted with 10 mL of CH₂Cl₂ and washed with 20 mL of H₂O.The aqueous fraction was extracted with two, 15-mL portions of CH₂Cl₂.The combined organic phases were then washed with 10 mL of satd aq NaClsolution, dried over MgSO₄, filtered, and concentrated to a yellow oil.Purification via column chromatography on silica gel (elution with 50%EtOAc/hexanes) afforded 0.029 g (34% over two steps) of Cmpd 11 as ayellow solid: ¹H NMR (CHLOROFORM-d, 400 MHz): δ 8.19 (br. s., 1H),7.82-7.85 (m, 1H), 7.17 (s, 1H), 6.78-6.83 (m, 2H), 6.62 (s, 2H),4.76-4.86 (m, 1H), 3.84-3.90 (m, 5H), 3.71-3.77 (m, 6H), 2.25-2.32 (m,1H), 1.88-2.00 (m, 7H), 1.74-1.83 (m, 4H), 1.65 (s, 3H), 1.68 (s, 3H),1.53 (d, J=12.6 Hz, 1H), 1.43 (dd, J=5.7, 0.7 Hz, 1H), 1.32-1.41 ppm (m,2H); LRMS (ESI) m/z [M+H]⁺ calcd for C₃₅H₄₂N₄O₉: 663.3; found: 663.3.

Example 12. Preparation of (Cmpd 12),dispiro[adamantane-2,4′-[1,3]dioxolane-2′,1″-cyclohexane]-3″-ylN-{2-methoxy-5-[1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl]phenyl}carbamate

Step 1: Preparation of Alkene Cmpd 12a, 2-Methylideneadamantane

A 200-mL, round-bottomed flask equipped with a stir bar, rubber septa,and an argon inlet needle was charged with a solution ofmethyltriphenylphosphonium iodide (3.39 g, 8.38 mmol, 1.2 equiv)dissolved in THF (31 mL). A solution of n-BuLi (1.42 M in THF) was addeddropwise to this suspension until the starting material dissolved and abright orange color persisted (ca. 8 mL, 11 mmol, 1.6 equiv). Thereaction mixture was stirred at rt for 15 minutes and then a solution of2-adamantanone (1.049 g, 6.98 mmol, 1 equiv) dissolved in THF (10 mL)was added dropwise to the reaction mixture while stirring under Ar.After stirring for 2 hours the reaction mixture was diluted with CH₂Cl₂and washed with H₂O. The aqueous layer was extracted with CH₂Cl₂ and theorganic phases were combined, washed with satd aq NaCl solution, driedover MgSO₄, filtered, and concentrated to a yellow oil which waspurified via silica chromatography eluting with 100% hexanes to yield0.680 g (66%) of Cmpd 12a as a fine white solid. ¹H NMR (400 MHz, CDCl₃)δ 4.51 (s, 2H), 2.49 (br. s., 2H), 1.92-1.97 (m, 2H), 1.85-1.92 (m, 4H),1.79-1.85 (m, 5H), 1.78 (br. s., 1H), ¹³C NMR (100 MHz, CDCl₃) δ 158.7,100.8, 77.5, 77.4, 76.9, 39.9, 39.3, 37.5, 28.5.

Step 2: Preparation of Alkene Cmpd 12b, 2-(hydroxymethyl)adamantan-2-ol

A 35-mL, round-bottomed flask was charged with Cmpd 12a (0.212 g, 1.4mmol, 1 equiv) dissolved in 5 mL of tert-butanol, and 5 mL of H₂O. Asolution of osmium tetroxide in (2.5% w/v in tert-butanol, 0.25 mL, 0.32mmol, 0.2 equiv) was added to this solution followed byN-methylmorpholine oxide (0.465 g, 4.0 mmol, 2.8 equiv). This mixturewas allowed to stir at rt for 12 hours then diluted with 20 mL of EtOAcand washed with 50 mL of satd aq NaHCO₃ solution. The aqueous phase wasextracted with two 50-mL portions of EtOAc. The organic phases werewashed with satd aq NaCl solution, dried over MgSO₄, and concentrated togive a light brown solid which was purified via silica chromatographyeluting with 40% EtOAc in Hexanes to yield 0.152 g of Cmpd 12b (58%). ¹HNMR (400 MHz, CD₃OD): δ 3.67 (s, 2H), 2.27 (d, J=11.9 Hz, 2H), 1.83-1.91(m, 2H), 1.77-1.83 (m, 4H), 1.71-1.77 (m, 4H), 1.50-1.58 ppm (m, 2H);LRMS (ESI) m/z [M+Na]⁺ calcd for C₁₁H₁₈O₂: 205.1; found: 204.9.

Step 3: Preparation of Dioxolane Cmpd 12c,tert-butyl({dispiro[adamantane-2,4′-[1,3]dioxolane-2′,1″-cyclohexane]-3″-yloxy})diphenylsilane

A 50 mL, 2-neck round-bottomed flask equipped with a stirbar, rubbersepta, and reflux condenser fitted with an argon inlet adapter wascharged with diol Cmpd 12b (0.126 g, 0.69 mmol, 1 equiv), ketone Cmpd 1a(0.260 g, 0.74 mmol, 1.07 equiv), CH₂Cl₂ (20 mL), and camphor sulfonicacid (0.038 g, 0.016 mmol, 0.24 equiv). The reaction mixture was heatedat reflux for 24 h, allowed to cool to rt, diluted with 20 mL of CH₂Cl₂,and washed with 25 mL of H₂O. The aqueous phase was extracted with two,25-mL portions of CH₂Cl₂. The combined organic phases were washed withsatd aq NaCl solution, dried over MgSO₄, filtered, and concentrated toafford a pale yellow oil. Purification via column chromatography onsilica gel (elution with 10% EtOAc/Hexanes) to yield 0.295 g (83%) ofCmpd 12c as clear oil. ¹H NMR (400 MHz, CDCl₃) δ 7.69-7.72 (m, 1H),7.67-7.69 (m, 1H), 7.39-7.46 (m, 1H), 7.38 (d, J=1.5 Hz, 1H), 7.35-7.37(m, 1H), 3.90-3.99 (m, 1H), 3.77 (dd, J=50.9, 9.5 Hz, 2H), 1.99-2.06 (m,1H), 1.86-1.94 (m, 1H), 1.82 (d, J=11.5 Hz, 1H), 1.69-1.77 (m, 2H), 1.66(br. s., 2H), 1.43-1.59 (m, 3H), 1.36-1.43 (m, 2H), 1.27-1.36 (m, 1H),1.05-1.10 ppm (m, 5H); LRMS (ESI) m/z [M+H]⁺ calcd for C₃₃H₄₄O₃Si:517.3; found: 517.3.

Step 4: Preparation of Alcohol Cmpd 12d,dispiro[adamantane-2,4′-[1,3]dioxolane-2′,1″-cyclohexane]-3″-ol

A 25-mL, round-bottomed flask equipped with a stir bar, rubber septa,and an argon inlet needle was charged with a solution of dioxolane Cmpd12c (0.139 g, 0.56 mmol, 1 equiv) in dry THF (6 mL) and cooled to 0° C.A solution of TBAF (1.0 M in THF, 2.8 mL, 2.8 mmol, 5 equiv) was addeddropwise to this solution while stirring at 0° C. The reaction wasstirred at 0° C. for 30 minutes, allowed to warm to rt, stirred at rtfor 19 hours, and then diluted with 20 mL of EtOAc and washed with 50 mLof H₂O. The aqueous layer was extracted with 30 mL of EtOAc. Thecombined organic phases were washed with satd aq NaCl solution, driedover MgSO₄, filtered, and concentrated to afford a clear oil.Purification via column chromatography on silica gel (elution with 25%EtOAc/hexanes) afforded 0.139 g (89%) of Cmpd 12d as a foamy, white oil:¹H NMR (400 MHz, CDCl₃): δ 3.98 (br. s., 1H), 3.86-3.92 (m, 2H), 2.67(br. s., 1H), 2.11-2.19 (m, 2H), 1.88 (d, J=3.8 Hz, 1H), 1.74-1.84 (m,7H), 1.66-1.72 (m, 3H), 1.54-1.62 (m, 7H), 1.44-1.54 ppm (m, 1H); LRMS(ESI) m/z [M+H]⁺ calcd for C₁₇H₂₆O₃: 279.2; found: 279.1.

Step 5: Preparation of Dioxolane Cmpd 12

Cmpd 12 was prepared in a manner analogous to the preparation of Cmpd 11(see Example 11) by reacting the requisite alcohol starting materialCmpd 12d (22 mg, 0.08 mmol, 1.16 equiv) with isocyanate (Compound 11a).Affording 0.014 g (31% over two steps) of Cmpd 12 as a yellow solid. ¹HNMR (400 MHz, CDCl₃): δ 7.78-7.87 (m, 1H), 7.19 (s, 1H), 6.73-6.82 (m,2H), 6.54-6.65 (m, 2H), 3.95 (s, 1H), 3.88 (s, 6H), 3.76 (s, 6H), 2.24(d, J=14.5 Hz, 2H), 2.14 (s, 1H), 2.06-2.13 (m, 1H), 1.78 (s, 3H), 1.82(s, 3H), 1.51-1.73 (m, 8H), 1.38 ppm (d, J=5.1 Hz, 2H); LRMS (ESI) m/z[M+H]⁺ calcd for C₃₆H₄₄N₄O₈: 661.3; found: 661.2.

Example 13. Preparation of (Cmpd 13),dispiro[adamantane-2,2′-[1,3]dioxolane-4′,1″-cyclohexane]-3″-ylN-{2-methoxy-5-[1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl]phenyl}carbamate

Step 1: Preparation of Alkene Cmpd 13a,tert-butyl[(3-methylidenecyclohexyl)oxy]diphenylsilane

A 25-mL, round-bottomed flask equipped with a stir bar, rubber septa,and an argon inlet needle was charged with a solution ofmethyltriphenylphosphonium iodide (0.266 g, 0.660 mmol, 2 equiv) in THF(3 mL). A solution of n-BuLi (1.42 M in THF) was added dropwise to thissuspension until the starting material dissolved and a bright orangecolor persisted (ca. 0.43 mL, 0.61 mmol, 1.9 equiv). This solution wasstirred at rt for 15 minutes at and then a solution of ketone Cmpd 1a(115 mg, 0.33 mmol, 1 equiv) in THF (2 mL) was added dropwise to thereaction mixture. The reaction mixture was allowed to stir at rt for 5 hthen diluted with CH₂Cl₂ and washed with H₂O. The aqueous layer wasextracted with CH₂Cl₂ and the combined organic phases were washed withsatd aq NaCl solution, dried over MgSO₄, filtered, and concentrated toafford an oil. Purification via column chromatography on silica gel(elution with 10% EtOAc/hexanes) afforded 0.050 g (44%) of Cmpd 13a as awhite solid: ¹H NMR (400 MHz, CDCl₃): δ 7.65-7.78 (m, 3H), 7.30-7.49 (m,5H), 4.64 (d, J=1.1 Hz, 1H), 4.52 (d, J=1.1 Hz, 1H), 3.75 (ddd, J=8.7,5.0, 4.0 Hz, 1H), 2.34 (dd, J=12.8, 4.2 Hz, 1H), 2.05-2.19 (m, 2H),1.93-2.05 (m, 1H), 1.71-1.84 (m, 2H), 1.46-1.61 (m, 1H), 1.12-1.33 (m,2H), 1.04-1.12 ppm (m, 9H); ¹³C NMR (100 MHz, CDCl₃): δ 146.9, 136.0,136.0, 135.0, 134.9, 134.9, 134.1, 133.9, 129.7, 129.7, 129.0, 128.8,127.7, 127.6, 109.1, 72.1, 44.5, 35.1, 34.5, 27.2, 24.1, 19.4 ppm.

Step 2: Preparation of Diol Cmpd 13b,3-[(tert-butyldiphenylsilyl)oxy]-1-(hydroxymethyl)cyclohexan-1-ol

A 35-mL, round-bottomed flask was charged with a solution of alkene Cmpd13a (0.050 g, 0.14 mmol, 1 equiv) in THF (2 mL). A solution of osmiumtetroxide (2.5% w/v in tert-butanol, 6 μL, 0.007 mmol, 0.05 equiv) wasthen added followed by N-methylmorpholine oxide (0.026 g, 0.2 mmol, 1.6equiv). This mixture was allowed to stir at rt for 27 hours then dilutedwith EtOAc and washed with saturated NaHCO₃. The aqueous phase wasextracted with two portions of EtOAc. The combined organic phases werewashed with satd aq NaCl solution, dried over MgSO₄, filtered, andconcentrated. Purification via column chromatography on silica gel(elution with 40% EtOAc/hexanes) afforded 0.034 g of Cmpd 13b (63%). ¹HNMR (400 MHz, CDCl3): δ 7.62-7.78 (m, 3H), 7.32-7.51 (m, 5H), 4.21-4.30(m, 1H), 4.03 (s, 1H), 3.35-3.51 (m, 2H), 3.25-3.35 (m, 1H), 2.02-2.22(m, 2H), 1.66-1.84 (m, 2H), 1.54-1.66 (m, 1H), 1.44-1.54 (m, 1H),1.16-1.39 (m, 4H), 1.02-1.16 ppm (m, 9H)¹³C NMR (CHLOROFORM-d, 100 MHz):δ 136.0, 136.0, 136.0, 133.4, 130.2, 130.2, 129.8, 129.7, 128.0, 128.0,127.7, 127.7, 73.5, 72.7, 71.1, 70.2, 69.1, 43.1, 38.5, 35.4, 34.1,33.3, 32.5, 27.2, 27.2, 19.5, 19.3, 15.9 ppm. LRMS (ESI) m/z [M+H]⁺calcd for C₂₃H₃₂O₃Si: 385.2; found: 385.2.

Step 3: Formation of Dioxolane Cmpd 13c,tert-butyl({dispiro[adamantane-2,2′-[1,3]dioxolane-4′,1″-cyclohexane]-3″-yloxy})diphenylsilane

A 35-mL, 2-necked round-bottomed flask equipped with a stir bar, rubbersepta, and a reflux condenser fitted with an argon inlet was chargedwith diol Cmpd 13b (0.035 g, 0.09 mmol, 1 equiv), 2-adamantanone (0.033g, 0.2 mmol, 2.4 equiv), camphor sulfonic acid (0.038 g, 0.016 mmol,0.24 equiv), and CH₂Cl₂ (4 mL). The reaction mixture was heated toreflux for 45 be allowed to cool to rt, and then diluted with CH₂Cl₂ andwashed with H₂O. The aqueous layer was extracted with two portions ofCH₂Cl₂. The combined organic phases were washed with satd aq NaClsolution, dried over MgSO₄, filtered, and concentrated to a light yellowoil. Purification via column chromatography on silica gel (elution with5% EtOAc/hexanes) afforded 0.043 g (91%) of Cmpd 13c as clear oil: ¹HNMR (400 MHz, CDCl₃): δ 7.65-7.71 (m, 3H), 7.30-7.49 (m, 5H), 4.09 (s,1H), 3.75 (dd, J=15.4, 8.2 Hz, 1H), 3.50 (d, J=8.1 Hz, 1H), 3.32-3.43(m, 1H), 3.17 (dd, J=8.2, 0.9 Hz, 1H), 1.83-2.02 (m, 4H), 1.49-1.79 (m,14H), 1.19-1.46 (m, 3H), 1.06 (s, 9H), 0.82-1.01 ppm (m, 1H); ¹³C NMR(100 MHz, CDCl₃): δ 136.0, 136.0, 136.0, 134.7, 134.6, 129.8, 129.8,129.7, 127.8, 127.7, 127.7, 127.7, 111.2, 80.9, 80.8, 74.3, 71.8, 70.8,69.9, 47.0, 38.6, 38.5, 38.0, 37.5, 37.5, 36.3, 36.1, 35.2, 35.1, 35.1,35.0, 34.8, 34.8, 27.3, 27.2, 27.0, 21.1, 19.4, 19.3 ppm.

Step 4: Preparation of Alcohol Cmpd 13d,dispiro[adamantane-2,4′-[1,3]dioxolane-2′,1″-cyclohexane]-3″-ol

A 20-mL, scintillation vial equipped with a stir bar, rubber septa, andan argon inlet needle was charged with a solution of dioxolane Cmpd 13c(0.041 g, 0.08 mmol, 1 equiv) in THF (2 mL) and cooled to 0° C. Asolution of TBAF (1.0 M in THF, 0.4 mL, 0.4 mmol, 5 equiv) was addeddropwise and the reaction mixture was stirred at 0° C. for 30 min,allowed to warm to rt over 1 h, and stirred at rt for 19 h. The reactionmixture was diluted with EtOAc and washed with H₂O. The aqueous phasewas extracted with EtOAc and the combined organic phases were washedwith satd aq NaCl solution, dried over MgSO₄, filtered, and concentratedto a clear oil. Purification via column chromatography on silica gel(elution with 25% EtOac/hexanes) afforded 0.020 g of Cmpd 13d (91%) as afoamy, white oil: ¹H NMR (400 MHz, CDCl₃): δ 3.94-4.07 (m, 1H),3.67-3.81 (m, 2H), 1.84-2.09 (m, 7H), 1.71-1.84 (m, 5H), 1.57-1.71 (m,6H), 1.39-1.57 (m, 2H), 1.13-1.39 ppm (m, 2H); ¹³C NMR (400 MHz, CDCl₃):δ 113.1, 81.0, 74.6, 74.5, 68.5, 67.9, 45.5, 41.5, 38.5, 38.2, 37.8,37.4, 37.3, 36.1, 35.9, 35.2, 35.1, 35.0, 33.0, 27.3, 27.1, 27.0, 26.9,20.5, 17.4 ppm; LRMS (ESI) m/z [M+H]⁺ calcd C₁₇H₂₆O₃: 279.2; found:279.1.

Step 5: Preparation of Dioxolane Cmpd 13e,dispiro[adamantane-2,2′-[1,3]dioxolane-4′,1″-cyclohexane]-3″-yl4-nitrophenyl carbonate

A 20-mL scintillation vial equipped with a stir bar, rubber septa, andan argon inlet needle was charged with a solution of alcohol Cmpd 13d(0.020 g, 0.07 mmol, 1 equiv) in CH₂Cl₂ and triethylamine (0.02 mL, 0.29mmol, 2.95 equiv) and was cooled to 0° C. p-Nitrophenyl chloroformate(0.020 g, 0.10 mmol, 1.38 equiv) and 4-dimethylaminopyridine (0.005 g,0.04 mmol, 0.57 equiv) were each added as a solid in a single portion.The reaction mixture was stirred at 0° C. for 20 minutes, allowed towarm to rt, and stirred at rt for 49 h. The reaction mixture was dilutedwith 10 mL of EtOAc and washed with four 15-mL portions of saturated aqNaHCO₃ solution and one 20-mL portion of satd aq NaCl solution, thendried over MgSO₄, filtered, and concentrated to give a pale yellow oil.Purification via column chromatography on silica gel (elution with 15%EtOAc/hexanes with 1% Et₃N) afforded 0.010 g (31%) of Cmpd 13e. ¹H NMR(400 Mz, CDCl₃): δ 8.25-8.32 (m, 1H), 7.36-7.43 (m, 2H), 5.02-5.12 (m,1H), 4.60-4.70 (m, 1H), 3.74-3.85 (m, 2H), 2.17-2.25 (m, 1H), 2.13 (dd,J=12.5, 4.1 Hz, 1H), 1.90-2.07 (m, 5H), 1.82-1.87 (m, 1H), 1.73-1.82 (m,4H), 1.60-1.73 (m, 8H), 1.52-1.60 (m, 2H), 1.23-1.32 ppm (m, 2H); LRMS(ESI) m/z [M+H]⁺ calcd C₂₄H₂₉NO₇: 444.2; found: 444.3.

Step 6: Preparation of Dioxolane Cmpd 13

A 4-mL glass vial equipped with a stir bar, rubber septa, and an argoninlet needle containing p-nitrophenyl carbonate Cmpd 13e (0.008 g, 0.02mmol, 1.0 equiv) was charged sequentially with a solution of2-methoxy-5-[1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl]aniline(Odlo, K.; Hentzen, J.; dit Chabert, J. F.; Ducki, S.; Gani, O. a B. S.M.; Sylte, I.; Skrede, M.; Florenes, V. A.; Hansen, T. V. Bioorg. Med.Chem. 2008, 16, 4829-4838)_(0.010 g, 0.03 mmol, 1.6 equiv) in DMF (0.5mL), DMAP (0.002 g, 0.02 mmol, 1 equiv), and DIPEA (0.02 mL, 0.1 mmol, 6equiv). The reaction was heated at 90° C. for 73 h while stirring underargon then allowed to cool to rt, diluted with 12 mL of Et₂O and washedwith three 15-mL portions of 1 M aq NaOH solution followed by 10 mL ofsatd aq NaCl solution. The organic phase was dried over MgSO₄, filtered,and concentrated. Purification via column chromatography on silica gel(gradient elution with 15-75% EtOAc/hexanes) afforded 0.014 g (31%) ofCmpd 13 as a yellow solid: ¹H NMR (300 MHz, CDCl₃): δ 8.23 (d, J=8.3 Hz,1H), 7.85 (s, 1H), 7.18 (d, J=13.9 Hz, 1H), 6.80 (s, 1H), 6.62 (s, 2H),5.01-5.13 (m, 1H), 3.89 (d, J=1.7 Hz, 5H), 3.79-3.85 (m, 2H), 3.73-3.79(m, 5H), 2.02-2.13 (m, 2H), 1.96 (d, J=10.4 Hz, 3H), 1.76 (br. s., 6H),1.68 (br. s., 10H), 1.22-1.32 ppm (m, 3H); LRMS (ESI) m/z [M+H]⁺ calcdfor C₃₆H₄₄N₄O₈: 661.3; found: 661.2.

Example 14. Preparation of (Cmpd 14),dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-3″-ylN-[1-(chloromethyl)-3-[(2E)-3-(4-methoxyphenyl)prop-2-enoyl]-1H,2H,3H-benzo[e]indol-5-yl]carbamate

Step 1: Preparation of Isocyanate Cmpd 14a,(2E)-1-[1-(chloromethyl)-5-isocyanato-1H,2H,3H-benzo[e]indol-3-yl]-3-(4-methoxyphenyl)prop-2-en-1-one

A 15-mL, re-sealable tube equipped with a stir bar, rubber septa, and anargon inlet needle was charged with a solution of triphosgene (0.021 g,0.1 mmol, 1.2 equiv.) in anhydrous EtOAc (2 mL). To this solution wasadded a solution of(2E)-1-[5-amino-1-(chloromethyl)-1H,2H,3H-benzo[e]indol-3-yl]-3-(4-methoxyphenyl)prop-2-en-1-one(Yang, S.; Denny, W. a. J. Org. Chem. 2002, 67, 8958-8961) (0.023 g, 0.1mmol, 1.0 equiv) in CH₂Cl₂ (4 mL) dropwise over 10 minutes. The rubberseptum was then quickly replaced for a threaded Teflon cap. The reactionmixture was heated at 75° C. (behind a blast shield) for 17 h, allowedto cool to rt, and then transferred to a heat-gun dried, 35-mL,round-bottomed flask, and concentrated to afford Cmpd 14a as an orangesolid that was further dried on high vacuum for at least 1 hour prior touse in subsequent reactions. This material was used in the next stepwithout further purification.

Step 2: Preparation of Carbamate Cmpd 14

A 35-mL, round-bottomed flask equipped with a stir bar, rubber septa,and an argon inlet needle containing the isocyanate (Cmpd 14a) preparedin the previous step was charged with a solution of alcohol Cmpd 1c(0.036 g, 0.1 mmol, 2.2 equiv.) in DMF (2 mL) (which had been dried onactivated molecular sieves while stirring under argon for 30 minutes).This solution was stirred at rt for 45 h. The reaction mixture wasdiluted with 15 mL of EtOAc and washed with two 20-mL portions of H₂Ofollowed by 20 mL of satd aq NaCl solution. The organic phases weredried over MgSO₄, filtered, and concentrated to afford a yellow oil.Purification via column chromatography on silica gel (elution with 25%EtOAc/hexanes) afforded 0.012 g (30%) of Cmpd 14 as a yellow solid: ¹HNMR (400 MHz, CDCl₃): δ 7.88-7.94 (m, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.60(br. s., 1H), 7.51-7.57 (m, 1H), 7.41-7.48 (m, 1H), 6.91-6.98 (m, 1H),6.79 (br. s., 1H), 5.06 (d, J=2.7 Hz, 1H), 4.92 (br. s., 1H), 4.56 (d,J=9.2 Hz, 1H), 4.46-4.52 (m, 1H), 4.36-4.45 (m, 1H), 3.96 (d, J=11.2 Hz,1H), 3.85-3.89 (m, 2H), 3.44-3.53 (m, 1H), 3.08 (t, J=5.8 Hz, 1H),2.25-2.43 (m, 2H), 2.12 (br. s., 2H), 1.89-2.07 (m, 9H), 1.66-1.88 (m,11H), 0.83-0.95 ppm (m, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 207.2, 179.2,161.5, 144.2, 130.1, 127.9, 127.6, 124.9, 114.5, 112.1, 111.8, 108.9,108.7, 77.7, 77.4, 77.2, 76.8, 73.4, 72.3, 55.6, 46.2, 41.4, 40.3, 40.1,37.0, 36.6, 36.5, 36.4, 36.0, 35.1, 35.0, 35.0, 34.0, 31.1, 30.8, 27.0,26.7, 26.0, 22.9, 20.0 ppm; LRMS (ESI) m/z [M+H]⁺ calcd forC₄₀H₄₃ClN₂O₇: 699.3; found: 699.3.

Example 15. Preparation of (Cmpd 15),dispiro[adamantane-2,4′-[1,3]dioxolane-2′,1″-cyclohexane]-3″-ylN-[1-(chloromethyl)-3-[(2E)-3-(4-methoxyphenyl)prop-2-enoyl]-1H,2H,3H-benzo[e]indol-5-yl]carbamate

This compound (Cmpd 15) was prepared in a manner analogous to trioxolaneconjugate Cmpd 14 by reacting the requisite alcohol Cmpd 12d (0.022 g,0.079 mmol, 1.19 equiv) with isocyanate Cmpd 14a. Affording 0.014 g(0.021 mmol, 31%) of Cmpd 15 as a yellow solid. ¹H NMR (400 MHz, CDCl₃):δ 7.87-7.96 (m, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.50-7.66 (m, 2H), 7.45(dd, J=8.2, 7.1 Hz, 1H), 6.90-7.00 (m, 2H), 5.03 (d, J=3.3 Hz, 1H), 4.58(d, J=11.0 Hz, 1H), 4.42 (br. s., 1H), 3.97 (d, J=11.4 Hz, 1H),3.90-3.95 (m, 1H), 3.87 (s, 2H), 3.49 (t, J=11.0 Hz, 1H), 2.26 (d,J=11.0 Hz, 2H), 2.18 (br. s., 2H), 1.74-1.90 (m, 5H), 1.66-1.74 (m, 3H),1.61 (br. s., 4H), 1.51 (dd, J=14.9, 5.0 Hz, 2H), 1.13 (dt, J=13.2, 7.3Hz, 1H), 0.98 (s, 1H), 0.78-0.96 ppm (m, 4H) LRMS (ESI) m/z [M+H]⁺ calcdfor C₄₁H₄₅ClN₂O₆: 697.3; found: 697.3.

Example 16. Preparation of (Cmpd 16),dispiro[adamantane-2,4′-[1,3]dioxolane-2′,1″-cyclohexane]-3″-ylN-{2-methoxy-5-[1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl]phenyl}carbamate

Step 1: Preparation of P-Nitrophenylcarbonate Cmpd 16a,dispiro[adamantane-2,4′-[1,3]dioxolane-2′,1″-cyclohexane]-3″-yl4-nitrophenyl carbonate

A solution of alcohol Cmpd 12d (0.027 g, 0.1 mmol, 1 equiv) andN,N-diisopropylethylamine (0.05 mL, 0.29 mmol, 2.95 equiv) in CH₂Cl₂ (2mL) was cooled at 0° C. while p-nitrophenyl chloroformate (0.047 g, 0.23mmol, 2.4 equiv) and 4-dimethylaminopyridine (0.011 g, 0.09 mmol, 0.92equiv) were added as solids in a single portion. The reaction mixturewas maintained at 0° C. for 20 minutes, allowed to warm to rt, stirredat rt for 48 h, then diluted with 10 mL of EtOAc and washed with four15-mL portions of satd aq NaHCO₃ solution and once with 20 mL of satd aqNaCl solution. The organic phase was dried over MgSO₄, filtered, andconcentrated to give a pale yellow oil. Purification via columnchromatography on silica gel (elution with 15% EtOAc/hexanes with 1%Et₃N) afforded 0.026 g (60%) of Cmpd 16a as a white foam: ¹H NMR (400MHz, CDCl₃) δ 8.28-8.30 (m, 1H), 8.26-8.28 (m, 1H), 7.40-7.42 (m 1H)7.38-7.40 (m, 1H), 4.91-4.99 (m, 1H), 3.92 (s, 2H), 2.18-2.25 (m, 2H),2.12-2.18 (m, 2H), 1.74-1.86 (m, 8H), 1.53-1.73 (m, 9H), 1.44-1.52 ppm(m, 2H); LRMS (ESI) m/z [M+H]⁺ calcd for C₂₄H₂₉NO₇: 444.2; found: 444.2.

Step 2: Preparation of Cmpd 16

To a solution of the p-nitrophenyl carbonate Cmpd 16a (0.027 g, 0.06mmol, 1.13 equiv) in DMF (2 mL) was added sequentially3′-deoxy-3′-fluorothymidine (0.013 g, 0.05 mmol, 1 equiv),4-dimethylaminopyridine (0.007 g, 0.06 mmol, 1 equiv), andN,N-diisopropylethylamine (0.06 mL, 0.32 mmol, 6 equiv). The reactionmixture was heated at 50° C. for 48 h, allowed to cool to rt, anddiluted with 10 mL of EtOAc and 15 mL of satd aq NaHCO₃ solution. Theorganic phase was separated and washed with three, 15-mL portions ofsatd aq NaHCO₃ and one 15-mL portion of satd aq NaCl solution, driedover MgSO₄, filtered, and concentrated. Purification via columnchromatography on silica gel (elution with 40-50% EtOAc/hexanes)afforded 0.015 g of Cmpd 16 (51%) as a clear film: ¹H NMR (400 MHz,CDCl₃) δ 8.54 (br. s., 1H), 7.36-7.42 (m, 1H), 6.45 (dd, J=9.1, 5.6 Hz,1H), 5.19 (d, J=5.1 Hz, 1H), 4.80-4.90 (m, 1H), 4.49 (br. s., 1H), 4.42(s, 1H), 4.38-4.40 (m, 1H), 4.36 (t, J=2.7 Hz, 1H), 3.89 (d, J=2.4 Hz,1H), 2.55-2.68 (m, 1H), 2.22-3.13 (m, 2H), 2.09-2.28 (m, 5H), 1.90-1.95(m, 3H), 1.73-1.84 (m, 7H), 1.54-1.72 ppm (m, 10H); LRMS (ESI) m/z[M+H]⁺ calcd for C₂₈H₃₇FN₂O₈: 549.6; found: 549.3.

Example 17: Preparation of (Cmpd 17),dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-3″-yl2-oxo-2H-chromen-7-yl carbonate

A 20-mL, scintillation vial equipped with a stirbar and screw cap wascharged with a solution of p-nitrophenyl carbonate Cmpd 6a (0.043 g,0.097 mmol, 1.0 equiv) in DMF (1.5 mL). 7-hydroxycoumarin (0.040 g, 0.25mmol, 2.6 equiv), i-Pr₂NEt (0.05 mL, 0.3 mmol, 3 equiv), and DMAP (0.005g, 0.04 mmol, 0.4 equiv) were added sequentially. The reaction mixturewas stirred at rt for 18 h. An additional portion of 7-hydroxycoumarin(0.017 g, 0.10 mmol, 1.1 equiv) and i-Pr₂NEt (0.05 mL, 0.3 mmol, 3equiv) was added and the reaction mixture was stirred at rt for anadditional 3 h. After 21 h total reaction time, the reaction mixture wasdiluted with 50 mL of Et₂O. The resulting solution was washedsequentially with 15 mL of 1 M aq HCl solution, five 15-mL portions of 1M aq NaOH, and 20 mL of satd aq NaCl solution. The organic phase wasdried over MgSO₄, filtered, and concentrated to afford a colorless oil.Purification via column chromatography on 12 g of silica gel (gradientelution with 2-25% EtOAc/hexanes) afforded 0.037 g (82%) of Cmpd 17 (asa 60:40 mixture of diastereomers) as a colorless oil: ¹H NMR (400 MHz,CDCl₃) δ 7.70 (d, J=9.5 Hz, 1H), 7.50 (d, J=8.6 Hz, 1H), 7.22 (dd,J=9.1, 2.1 Hz, 1H), 7.12-7.18 (m, J=1.9, 1.0, 1.0 Hz, 1H), 6.41 (d,J=9.5 Hz, 1H), 4.91-5.00 (m, 1H), 2.33-2.44 (m, 1H), 1.44-2.15 ppm (m,21H); LRMS (ESI) m/z [M+H]⁺ calcd for C₂₆H₂₈O₈: 469.2; found: 469.1. Apeak corresponding to the minor diastereomer was observed: ¹H NMR (400MHz, CDCl₃) δ 4.80-4.89 (m, 1H).

Example 18. Preparation of (Cmpd 18),dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-7-yl5-(dimethylamino)naphthalene-1-sulfonate

To a solution of adamantyl alcohol(dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-7-ol)(Vennerstrom, J. L.; Dong, Y.; Charman, S. A.; Wittlin, S.; Chollet, J.;Wang, X.; Srigraghavan, K.; Zhou, L.; Matile, H.; Charman, W. N. PatentWO/2009/091433, 2009)(0.15 g, 0.54 mmol, 1 equiv) and DMAP (0.065 g,0.54 mmol, 1 equiv) in pyridine (3 mL) at 0° C. was added dropwise asolution of dansyl chloride (0.29 g, 1.07 mmol, 2 equiv) in CH₂Cl₂ (0.2mL). The reaction was warmed slowly to room temperature and stirredovernight, at which time additional dansyl chloride (0.725 g, 1.35 mmol,5 equiv) was added and the reaction left to stir for an additional 72 h.The reaction mixture was then concentrated in vacuo, and the resultingresidue was dissolved with ethyl acetate and water. The aqueous layerwas separated and extracted with three 5-mL portions of EtOAc. Thecombined organic phases were washed with water and satd aq NaClsolution, dried over MgSO₄, filtered, and concentrated. Purification viacolumn chromatography on 12 g of silica gel (elution with 7%EtOAc/hexanes) to afford 0.079 g (29%) of Cmpd 18 (as a mixture ofstereoisomers) as a foamy, yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 8.56(dd, J=8.4, 3.6 Hz, 1H), 8.22-8.31 (m, 2H), 7.49-7.60 (m, 2H), 7.19 (dd,J=7.6, 3.2 Hz, 1H), 2.89 (s, 6H), 2.26-2.50 (m, 2H), 2.03-2.21 (m, 7H),1.79-1.91 (m, 2H), 1.50-1.70 (m, 10H), 1.30-1.45 (m, 2H); LRMS (ESI) m/z[M+H]⁺ calcd for C₂₈H₃₅NO₆: 514.7; found: 514.7.

Example 19. Preparation of (Cmpd 19),5-(dimethylamino)-N-[3-({dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-4″-yl}amino)propyl]naphthalene-1-sulfonamide

Step 1: Preparation of Diamine Cmpd 19a, tert-butylN-[3-({dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-4″-yl}amino)propyl]carbamate

To a solution of(dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-4″-one)(Tang, Y.; Dong, Y.; Karle, J. M.; DiTusa, C. A.; Vennerstrom, J. L. J.Org. Chem. 2004, 69, 6470-6473)(0.350 g, 1.26 mmol, 1 equiv) andN-Boc-1,3-propanediamine (0.260 g, 1.5 mmol, 1.2 equiv) indichloroethane (3 mL) was added sodium triacetoxyborohydride (0.400 g,1.89 mmol, 1.5 equiv). The reaction mixture was stirred at rt for 1 h.The reaction mixture was then diluted with 10 mL of CH₂Cl₂, washed with10 mL of satd aq NaHCO₃ solution and 20 mL of satd aq NaCl solution,dried over Na₂SO₄, filtered, and concentrated. Purification via columnchromatography on 25 g of silica gel (elution with 5% MeOH/CH₂Cl₂)afforded 0.550 g (>95%) of Cmpd 19a (as a mixture of diastereomers) as acolorless oil: ¹H NMR (400 MHz, CDCl₃) δ 5.13-5.17 (m, 0.14H), 3.22-3.23(m, 2H), 2.70-2.73 (m, 2H), 2.59 (m, 1H), 1.44-2.03 (m, 24H), 1.44 (s,9H): LRMS (ESI) m/z [M+H]⁺ calcd for C₂₄H₄₀N₂O₅: 437.3; found: 437.3.

Step 2: Preparation of Cmpd 19

Carbamate Cmpd 19a (0.300 g, 0.690 mmol, 1 equiv) was dissolved in a 4 Nsolution of HCl in dioxane (3.6 mL). The reaction mixture was stirred atrt for 30 min and then concentrated in vacuo. A quarter of the crudeproduct was dissolved in CH₂Cl₂ (0.5 mL) and treated with dansylchloride (0.047 g, 0.17 mmol) and triethylamine (0.06 mL, 0.4 mmol). Thereaction mixture was stirred overnight protected from light. Thereaction mixture was then loaded directly onto a silica gel column(gradient elution 2-5% MeOH/CH₂Cl₂) to provide 0.008 g (8% over twosteps) of Cmpd 19 as a foamy yellow solid: ¹H NMR (400 MHz, CDCl₃) δ8.49-8.55 (m, 1H), 8.20-8.33 (m, 2H), 7.47-7.59 (m, 2H), 7.15-7.21 (m,1H), 2.97-3.04 (m, 2H), 2.89 (s, 6H), 2.57-2.64 (m, 2H), 2.35-2.45 (m,1H), 1.48-2.02 (m, 22H), 1.25-1.34 (m, 2H); LRMS (ESI) m/z [M+H]⁺ calcdfor C₃₁H₄₃N₃O₅S: 570.3; found: 570.3.

Example 20. Preparation of (Cmpd 20),5-(dimethylamino)-N-{dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-7-yl}naphthalene-1-sulfonamide

Step 1: Preparation of Carbamate Cmpd 20a, tert-ButylN-(4-oxoadamantan-1-yl)carbamate

4-oxoadamantane-1-carboxylic acid (Sengupta, S.; Rajagopalan, S.;Belavagi, N.; Ramachandra, M. Preparation of 2, 4-diaminopyrimidinederivatives as protein kinase inhibitors. WO 201205993 10 May 2012)(0.699 g, 3.59 mmol, 1.0 equiv) was dried twice via azeotrope from 5 mLof toluene in a 25-mL recovery flask. The flask was equipped with astirbar, rubber septum, and argon inlet needle and was then purged withargon for 5 min. The flask was charged with toluene (15 mL) andtriethylamine (1.00 mL, 7.2 mmol, 2.0 equiv). The reaction mixture wascooled at 0° C. while diphenylphosphoryl azide (0.774 mL, 3.6 mmol, 1.0equiv) was added dropwise via syringe over ca. 4 min. The reactionmixture was stirred at 0° C. for 5 min, allowed to warm to rt over 10min, and then the rubber septum was quickly exchanged for a refluxcondenser fitted with an argon inlet adapter. The reaction mixture washeated at 90° C. for 1.5 h (gas evolution was observed within 5 min ofheating and continued for 1 h), allowed to cool to rt over 20 min, andconcentrated to afford a pale yellow oil.

The crude isocyanate prepared above was dissolved in tert-butanol (15mL) and the solution was partitioned equally into three 10-mL microwavereactor tubes each equipped with a stirbar and silicon cap. Each tubewas heated in a microwave reactor at 120° C. for 4 h. The reactionmixtures were combined and diluted with 50 mL of EtOAc and 20 mL of 1 Maq Na₂CO₃. The aqueous layer was separated and extracted with three20-mL portions of EtOAc. The organic phases were washed with 30 mL ofsatd aq NaCl solution, dried over MgSO₄, filtered, and concentrated toafford a colorless semi-solid. A solution of this material in 10 mL ofCH₂Cl₂ was deposited onto silica gel. The resulting free flowing powderwas loaded on top of a 25 g silica gel cartridge. Gradient elution with0-30% EtOAc/hexanes afforded 0.673 g (70%) of Cmpd 20a as a colorlesssolid with spectral data consistent with that previously reported: (WO2012059932)¹H NMR (400 MHz, CDCl₃) δ 4.50 (br. s., 1H), 2.55 (br. s,2H), 2.23-2.12 (m, 7H), 2.02-1.85 (m, 4H), 1.39 (s, 9H); LRMS (ESI) m/z[M+Na]⁺ calcd for C₁₅H₂₃NO₃: 288.2; found: 288.1.

Step 2: Preparation of Oxime Cmpd 20b, tert-ButylN-[4-(methoxyimino)adamantan-1-yl]carbamate

A 25-mL, recovery flask equipped with a stirbar was charged with ketoneCmpd 20a (0.502 g, 1.89 mmol, 1.0 equiv), methanol (6 mL), pyridine(0.305 mL, 3.78 mmol, 2.0 equiv), and methoxylamine hydrochloride (0.237g, 2.84 mmol, 1.5 equiv) and the reaction mixture was stirred at rtuntil all reagents dissolved. The reaction mixture was then partitionedequally into three 10-mL microwave tubes each equipped with a stibar andsilicon cap. The reaction mixtures were each heated in a microwavereactor at 90° C. for 30 min. The reaction mixtures were then combinedand concentrated. The resulting residue was diluted with 30 mL of EtOAcand 30 mL of 0.5 M aq HCl. The aqueous phase was separated and extractedwith three 30-mL portions of EtOAc. The combined organic phases werewashed with 30 mL of satd aq NaCl solution, dried over MgSO₄, filtered,and concentrated to afford a pale yellow oil. Purification via columnchromatography on 40 g of silica gel (gradient elution with 10-25%EtOAc/hexanes) afforded 0.474 g (85% yield) of Cmpd 20b as a whitesolid: ¹H NMR (400 MHz, CDCl₃) δ 4.40 (br s, 1H), 3.78 (s, 3H), 3.55 (brs, 1H), 2.63 (br s, 1H), 2.20-1.67 (m, 11H), 1.41 (s, 9H); LRMS (ESI)m/z [M+H]⁺ calcd for C₁₆H₂₆N₂O₃: 295.2; found: 295.2.

Step 3: Preparation of Trioxolane Cmpd 20c, tert-butylN-{dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-7-yl}carbamate

A 50-mL, recovery flask equipped with a stirbar was charged with oximeCmpd 20b (0.237 g, 0.805 mmol, 2.1 equiv), cyclohexanone (0.040 mL,0.408 mmol, 1.0 equiv), and CCl₄ (10 mL). The reaction mixture wascooled at 0° C. while ozone (0.6 L/min, 30% power) was bubbled throughthe solution for 30 min. The reaction mixture was maintained at 0° C.while being sparged with O₂, then was allowed to warm to rt over 10 minwhile being sparged with argon. The reaction mixture was concentrated toafford a white solid. Purification via column chromatography on 25 g ofsilica gel (gradient elution with 5-10% EtOAc/hexanes) afforded 0.081 g(55%) of Cmpd 20c as a white solid: ¹H NMR (CDCl₃, 400 MHz) δ 4.43-4.33(m, 1H), 2.17-2.10 (m, 1H), 2.07 (br. s., 2H), 2.04-1.89 (m, 6H), 1.85(d, J=12.8 Hz, 2H), 1.79-1.49 (m, 10H), 1.52-1.28 (m, 11H); LRMS (ESI)m/z [M+H]⁺ calcd for C₂₁H₃₃NO₅: 380.2; found: 380.2.

Step 4: Preparation of Cmpd 20

A 20-mL, scintillation vial equipped with a stirbar and screw cap wascharged with carbamate Cmpd 20c (0.073 g, 0.192 mmol, 1.0 equiv) and asolution of hydrochloric acid in dioxane (4 M, 1.80 mL, 7.21 mmol, 37.5equiv). The resulting mixture was stirred at rt for 30 min. The reactionmixture was diluted with 10 mL toluene and concentrated to a volume ofca 1 mL. The resulting mixture was diluted and concentrated twice from 5mL of toluene to afford a white solid. This material was used in thenext step without further purification.

A 20-mL, scintillation vial equipped with a stirbar and screw capcontaining the adamantylamine hydrochloride prepared above was chargedwith CH₂Cl₂ (1 mL) and N,N-diisopropylethylamine (0.101 mL, 0.6 mmol,3.0 equiv) and was stirred at rt for 5 min. Dansyl chloride (0.063 g,0.2 mmol, 1.2 equiv) was added in a single portion and the reaction wasstirred at rt for 2 h. The reaction mixture was diluted with 25 mL ofEtOAc and 25 mL of H₂O. The aqueous layer was separated and extractedwith 3, 20-mL portions of EtOAc. The combined organic phases were washedwith 25 mL of satd aq NaCl solution, dried over MgSO₄, filtered, andconcentrated to afford a yellow oil. A solution of this material in 5 mLof CH₂Cl₂ was deposited onto silica gel and the free flowing powder wastransferred to the top of a 12 g silica gel cartridge. Gradient elutionwith 0-25% EtOAc/hexanes afforded 0.068 g of Cmpd 20 (as a 67:33 mixtureof diastereomers) as a yellow solid: ¹H NMR (CDCl₃, 400 MHz) δ 8.54 (br.d, J=8.4 Hz, 1H), 8.35-8.26 (m, 2H), 7.55 (m, 2H), 7.20 (d, J=7.5 Hz,1H), 4.82 (br. s, 1H), 2.90 (s, 6H), 2.05 (br. s, 2H), 1.98-1.80 (m,5H), 1.78-1.48 (m, 13H), 1.47-1.34 (m, 3H); LRMS (ESI) m/z [M+H]f calcdfor C₂₈H₃₆N₂O₅S: 513.23; found: 513.3; Some resonances corresponding tothe minor isomer were observed: ¹H NMR (CDCl₃, 400 MHz) δ 8.26-8.21 (m,2H), 7.54-7.50 (m, 2H), 7.19 (d, J=7.3 Hz, 1H), 4.80 (br s, 1H).

Example 21. Preparation of (Cmpd 21),5-({dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,4″-piperidine]-1″-yl}sulfonyl)-N,N-dimethylnaphthalen-1-amine

A 20-mL, scintillation vial equipped with a stirbar and screw cap wascharged with tert-butyldispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,4″-piperidine]-1″-carboxylate(Vennerstrom, J. L.; Dong, Y.; Chollet, J.; Matile, H. Spiro and dispiro1,2,4-trioxolane antimalarials. Preparation ofspiro/dispiro-1,2,4-trioxolanes as antimalarial agents. U.S. Pat. No.6,486,199, 26 Nov. 2002)(0.092 g, 0.25 mmol, 1.0 equiv) and a solutionof hydrochloric acid in dioxanes (4 M, 2.0 mL, 8.0 mmol, 32 equiv). Thereaction mixture was stirred at rt for 20 min, diluted with 6 mL oftoluene, and concentrated to a volume of about 2 mL. The resultingmixture was then diluted with 6 mL of toluene and concentrated todryness to afford a white solid. This material was used in the next stepwithout further purification.

A 20-mL, scintillation vial containing the hydrochloride salt preparedabove (dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,4″-piperidinehydrochloride) was charged with THF (3 mL), andN,N-diisopropylethylamine (0.219 mL, 1.26 mmol, 5 equiv) and was stirredat rt for 5 min. Dansyl chloride (0.068 g, 0.25 mmol, 1.0 equiv) wasadded as a solid in a single portion and the reaction mixture wasstirred at rt for 1 h. The reaction mixture was diluted with 20 mL ofEtOAc and 20 mL of H₂O. The aqueous layer was separated and extractedwith three 20-mL portions of EtOAc. The combined organic phases werewashed with 30 mL of satd aq NaCl solution, dried over MgSO₄, filtered,and concentrated to afford a yellow foamy solid. Purification via columnchromatography on 12 g of silica gel (gradient elution with 0-20%EtOAc/Hex) afforded 0.104 g (83%) of Cmpd 21 as a yellow solid: ¹H NMR(CDCl₃, 400 MHz) δ 8.57 (d, J=8.4 Hz, 1H), 8.35 (d, J=8.6 Hz, 1H), 8.21(dd, J=0.9, 7.3 Hz, 1H), 7.49-7.59 (m, 2H), 7.19 (d, J=7.5 Hz, 1H),3.45-3.54 (m, 2H), 3.24 (ddd, J=4.1, 8.1, 12.5 Hz, 2H), 2.89 (s, 6H),1.62-2.11 (m, 18H); LRMS (ESI) m/z [M+H]⁺ calcd for C₂₇H₃₄N₂O₅S: 499.2;found: 499.2.

Example 22. Preparation of (Cmpd 22),dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-3″-ylN-[(1S)-1-{[(2S,3S,4R,5R)-5-[6-(dimethylamino)-9H-purin-9-yl]-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]carbamoyl}-2-(4-methoxyphenyl)ethyl]carbamate

A 20-mL scintillation vial equipped with a stir bar, septa, and argoninlet was charged with Puromycin dihydrochloride from Streptomycesalboniger (0.031 g, 0.1 mmol, 1.0 equiv.), 4-dimethylaminopyridine (ca.0.001 g, 0.0 mmol, 0.1 equiv.), and 4-nitrophenyl carbonate Cmpd 6a(0.025 g, 0.1 mmol, 1.0 equiv.) and the atmosphere was replaced withargon. This material was then dissolved in N,N-dimethylformamide (2.000ml) and N,N-diisopropylethylamine (0.050 ml, 0.3 mmol, 5.1 equiv.) wasadded to this solution. The reaction mixture was allowed to stir at roomtemperature under argon for 4 hours then diluted with 10 mL of EtOAc andwashed with three, 15-mL portions of sat. NaHCO₃. The aqueous layer wasback extracted with 20 mL of EtOAc and the organic layers were combined,washed with 20 mL of satd aq NaCl solution, and then dried over MgSO₄,filtered, and concentrated to afford a light yellow oil. Purificationvia column chromatography on 12 g of silica gel (gradient elution with10-100% EtOAc/Hex) and re-purification of mixed fractions on 12 g ofsilica gel (gradient elution with 5-10% MeOH/DCM) afforded 26 mg (61%)of Cmpd 22 as a white solid: ¹H NMR (CDCl₃, 400 MHz) δ: 8.03-8.07 (m,1H), 7.97 (s, 1H), 7.15 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 6.62(br. s., 1H), 5.52 (d, J=4.4 Hz, 1H), 5.22 (br. s, 1H), 4.84 (br. s.,1H), 4.73-4.79 (m, 1H), 4.35-4.48 (m, 2H), 4.04-4.10 (m, 1H), 3.85-3.94(m, 1H), 3.78 (s, 3H), 3.70 (d, J=12.6 Hz, 1H), 3.59 (br. s., 1H),3.35-3.54 (m, 3H), 3.03-3.12 (m, 1H), 2.89-3.00 (m, 2H), 2.13-2.29 (m,2H), 1.94 (s, 3H), 1.99 (s, 2H), 1.88 (br. s., 2H), 1.80 (d, J=14.8 Hz,3H), 1.64-1.76 (m, 7H), 1.61 (br. s., 2H); LRMS (ESI) m/z [M+H]⁺ calcdfor C₃₉H₅₁N₇O₁₀: 778.4; found: 778.3.

Example 23. Preparation of (Cmpd 23),Dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-3″-ylN-(2-amino-2-methylpropyl)carbamate

A 20-mL scintillation vial was charged with carbonate 1 (0.300 g, 0.673mmol, 1.0 equiv), N,N-dimethylformamide (2 mL),N,N-diisopropylethylamine (0.235 mL, 1.35 mmol, 2 equiv).2-Methylpropane-1,2-diamine (0.105 mL, 1.01 mmol, 1.5 equiv) was addedin a single portion via microliter pipettor. The reaction was stirred atrt for 1 h. The reaction mixture was diluted with 30 mL of EtOAc andwashed with four 15-mL portions of 1 M aq NaOH solution (until aqueouswas no longer bright yellow), washed with 20 mL of satd aq NaCl, driedover MgSO4, filtered, and concentrated to afford a yellow oil.Purification via column chromatography on 25 g of silica gel (75-100%EtOAc/hexanes and then 0-15% MeOH/CH2Cl2) afforded 0.248 g (93%) ofcarbamate 23 (>95:5 dr) as a yellow foamy/sticky oil: IR (neat) 3343,2933, 2916, 2859, 1702, 1560, 1542, 1452, 1352, 1298, 1250, 1122, 1146,1114, 1087, 1067, 142, 1021, 1010, 929, 774 cm-1; 1H NMR (400 MHz,CDCl3) δ=5.10 (br. t, J=5.9 Hz, 1H), 4.68-4.78 (m, 1H), 3.01-3.12 (m,2H), 2.26 (dt, J=13.0, 2.2 Hz, 1H), 1.44-2.05 (m, 20H), 1.21-1.35 (m,1H), 1.12 ppm (s, 6H); 13C NMR (100 MHz, CDCl3) δ 156.5, 111.7, 109.0,71.1, 52.4, 50.6, 40.5, 37.0, 36.5, 35.1, 35.0, 34.9, 34.0, 31.0, 28.3,28.2, 27.1, 26.7, 20.0; HRMS (ESI) m/z [M+H]⁺ calcd for C₂₁H₃₄N₂O₅:395.2540; found: 395.2526.

Example 24. Preparation of (Cmpd 24), tert-butylN-[(3″R,4′R)-3″-[(tert-butyldiphenylsilyl)oxy]dispiro[adamantane-2,2′-[1,3,5]trioxolane-4′,1″-cyclohexane]-7-yl]carbamate

A 50-mL pear shaped flask equipped with a stirbar was charged withketone 1a (300 mg, 0.851 mmol, 1 equiv), CCl₄ (12 mL), and oxime 20b(500 mg, 1.70, mmol, 2 equiv) and was stirred at rt until solubilized.The reaction mixture was cooled to 0° C. while ozone was bubbled throughat 0.6 L/min, 30% power for 1 h. Additional oxime 20b (175 mg, 0.594mol, 0.7 equiv) was added in a single portion and bubbling of ozone wascontinued for 40 min. Additional oxime 20b (100 mg, 0.339 mmol, 0.4equiv) was added in a single portion and ozone was bubbled through thesolution at 0 deg C. for an additional 1 h. The reaction mixture wasthen concentrated to afford a white solid. A solution of this materialin 10 mL of DCM was deposited onto 5 g of silica gel. The resulting freeflowing powder was loaded atop an 80 g column of silica gel. Gradientelution (1CV 0-10%, 5CV 10%, 5CV 15% EtOAc/hexanes) afforded 306 mg,(57%) of trioxolane 24 as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ7.71-7.75 (m, 1H), 7.64-7.70 (m, 3H), 7.34-7.45 (m, 6H), 3.73-3.84 (m,1H), 2.04-2.16 (m, 1H), 1.84-2.03 (m, 8H), 1.66-1.83 (m, 4H), 1.59 (br.s., 4H), 1.40-1.46 (m, 8H), 1.20-1.30 (m, 1H), 1.08 (s, 2H), 1.05-1.08(m, 7H); ¹³C NMR (100 MHz, CDCl3) δ: 136.0, 135.9, 135.0, 134.6, 134.6,129.9, 129.8, 129.7, 127.9, 127.8, 127.7, 110.2, 109.7, 109.7, 69.9,49.8, 49.4, 43.9, 43.8, 39.2, 38.9, 37.3, 37.3, 37.1, 37.0, 34.5, 33.9,33.7, 33.6, 33.5, 28.7, 28.1, 27.7, 27.2, 26.8, 20.1, 19.3, 19.2. LRMS(ESI) m/z [M+H]⁺ calcd for C₃₇H51NO₆Si: 634.9; found: 634.4.

TABLE 1 Biological Activity Activity Target EC50 (Cell Example #Structure (nM) Line) Example 1

   14.3 P. falc Cmpd 2b

   408 P. falc Example 2

   10.7 P. falc Example 3

   65.7 P. falc Example 4

   147 P. falc Example 5

    5.9 P. falc W2 Example 6

   17.1 P. falc W2 Example 7

P. falc Example 8

    8      15      21 P. falc HB3 P. falc DD2 P. falc 3D7 Example 9

   29      15.7      23.3 P. falc D10 P. falc D10 P. falc D10 LiteratureCompound A

   70 P. falc D10 Example 10

   94      188      188 P. falc HB3 P. falc DD2 P. falc 3D7 LiteratureCompound B

   11     9    10    10     >1000 HeLa PC-3 MCF-7 MB- MDA- 231 P. falcW2 Example 11

   57    26    24    42        34 HeLa PC-3 MCF-7 MB- MDA- 231 P. falcW2 Example 12

>1000 >1000 >1000 >1000 HeLa PC-3 MCF-7 P. falc W2 Example 13

>1000 >1000 >1000 >1000 >1000     >1000 HeLa U87MG PC-3 MCF-7 MB- MDA-231 P. falc W2 Literature Compound C

    3    11     5     0.45 IMR90 HeLa U87MG P. falc W2 Example 14

   100    105    40     2.8 IMR90 HeLa U87MG P. falc W2 Example 15

>1000 >1000    41 IMR90 HeLa P. falc W2 Example 16

Example 17

   25.3 P. falc D10 Example 18

   17.9 P. falc FCB Example 19

   14.6 P. falc FCB Example 20

   11.4 P. falc DD2 Example 21

   54.2 P. falc DD2 Puromycin dihydrochloride from Streptomycesalboniger

   783   1696    569        25.3 HeLa IMR90 MB- MDA- 231 P. falc DD2Example 22

  3212   6979   5272        12.7 HeLa IMR90 MB- MDA- 231 P. falc DD2Example 23

 5 nM P. falc W2 Example 24

Example 25

27 nM P. falc W2

TABLE 2 Additional compounds (prodrugs) being made and tested. Drug/det.Ag./prot comment

Phosphor- amidate mustard

Phosphor- amidate mustard Double release variant

Phosphor- amidate mustard Extended linker variant

Phosphor- amidate mustard Extended linker variant

melphalan

gemcitabine

fludarabine

cytarabine

Irinotecan Extended linker

Topotecan Extended linker

centanamycin

puromycin

Epothilone B Extended linker

Duocarmycin analog Folate- receptor targeted conjugate

Duocarmycin analog Extended linker type

Duocarmycin analog Extended linker type

Combreta- statin analog Folate- receptor targeted conjugate

Duocarmycin analog Folate- receptor targeted conjugate

vinblastine Extended linker type

various

Various Extended linker type

tafenoquine

antimalarial HDAC inhibitor

HDAC inhibitor Extended linker type

Bestatin and analogs Extended linker type

Bestatin and analogs (metallo- protease inhibitor)

Metallo- protease inhibitor

metallo- protease inhibitor Extended linker

antimalarial (KAF-156)

antimalarial

antimalarial

Useful synthetic building block

Useful synthetic building block

Useful synthetic building block

Useful synthetic building block

Useful reagent for conjuga- tion to targeting moiety

Useful reagent for conjuga- tion to targeting moiety

FLT (PET imaging agent)

Antibody drug conjugate based on synthetic- ally accessible trioxolanelinker

Antibody drug conjugate based on synthetic- ally accessible trioxolanelinker

ciprofloxacin Targeting moiety is a bacterial sidero- phore

An oxazoli- dinone anti- bacterial Targeting moiety is a bacterialsidero- phore

gemcitabine Targeting moiety is a bacterial sidero- phore

Phosphor- amidate mustard Targeting moiety is a bacterial sidero- phore

Generic targeted drug conjugate employing a syn- thetically accessibletrioxolane linker

Generic targeted drug conjugate employing a syn- thetically accessibletrioxolane linker

Generic targeted drug conjugate employing a syn- thetically accessibletrioxolane linker

Generic targeted drug conjugate employing a syn- thetically accessibletrioxolane linker

Example 25. Fluorescence Microscopy Studies

In order to further study the fate of fragmenting compounds as describedherein within cultured parasites, fluorescence microscopy studies can beconducted. For example, the 4-nitrobenzo-2-oxa-1,3,-diazole (NBD)fluorophore has been used previously in studies of artemisinin (Stockset al., 2007, Angewandte Chemie International Edition,46(33):6278-6283.) and remains fluorescent over a wide pH range,including the acidic pH (˜5) of the P. falciparum food vacuole.Microscopes, and techniques thereof, most relevant to the experiments tobe conducted include an inverted epifluorescence microscope optimizedfor time lapse imaging, and a spinning disk confocal microscope. Bothmicroscopes can be equipped with temperature-, humidity-, andCO₂-controlled incubators, and both have been used successfully forimaging P. falciparum-infected erythrocytes. The epifluorescencemicroscope can have, for example, a hardware autofocus system (NikonPerfect Focus) and be optimized for long-term time lapse imaging. Theconfocal microscope can be optimized, for example, for high detectionsensitivity, with a back-thinned EMCCD camera (Photometrics Cascade II)which can be useful for observing the more subtle effects of biologicalaction of compounds on cultured parasites. Additional studies caninvolve combinations of compounds as described herein and iron chelatingreagents. The fluorescence, or lack thereof, of P. falciparum-infectedcells pre-treated with iron chelating reagents prior to contact withfluorophoric compounds described herein can demonstrate the specificrole of iron in the scission of the prodrug.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

What is claimed is:
 1. A compound having the formula:

wherein L¹-R¹ is —H; L², L³, L⁴, L⁶, L⁷, L⁸, and L⁹ are each a bond; R²,R³, R⁴, R⁶, R⁷, R⁸, and R⁹ are each hydrogen; L¹⁰ is —CH₂—; L⁵ isindependently selected from a bond, —N(R¹⁷)—, —N(R¹⁷)C(O)O—, —O—, —S—,—OC(O)—, —OC(O)N(R¹⁷)—, —OC(O)O—, —OSO₂—, —C(O)N(R¹⁷)—, —N(R¹⁷)C(O)—,—S(O)₂N(R¹⁷)—, —N(R¹⁷)S(O)₂—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene; R¹⁷ is independentlyhydrogen, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; and R⁵ is independently amonovalent form of GDC-0973, a monovalent form of selumetinib, amonovalent form of ARRY-162,


2. The compound of claim 1, wherein L⁵ is a bond.
 3. The compound ofclaim 1, wherein L⁵ is —OC(O)—.
 4. The compound of claim 1, wherein R⁵is a monovalent form of GDC-0973.
 5. The compound of claim 1, wherein R⁵is a monovalent form of selumetinib.
 6. The compound of claim 1, whereinR⁵ is a monovalent form of ARRY-162.
 7. The compound of claim 1, whereinR⁵ is


8. The compound of claim 1, wherein R⁵ is


9. The compound of claim 1, wherein the compound has the formula:


10. The compound of claim 1, wherein the compound has the formula:


11. A pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and a compound of claim
 1. 12. A pharmaceuticalcomposition comprising a pharmaceutically acceptable excipient and acompound of claim
 2. 13. A pharmaceutical composition comprising apharmaceutically acceptable excipient and a compound of claim
 3. 14. Apharmaceutical composition comprising a pharmaceutically acceptableexcipient and a compound of claim
 4. 15. A pharmaceutical compositioncomprising a pharmaceutically acceptable excipient and a compound ofclaim
 5. 16. A pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and a compound of claim
 6. 17. A pharmaceuticalcomposition comprising a pharmaceutically acceptable excipient and acompound of claim
 7. 18. A pharmaceutical composition comprising apharmaceutically acceptable excipient and a compound of claim
 8. 19. Apharmaceutical composition comprising a pharmaceutically acceptableexcipient and a compound of claim
 9. 20. A pharmaceutical compositioncomprising a pharmaceutically acceptable excipient and a compound ofclaim 10.